* 107770

LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 1; LRP1


Alternative titles; symbols

LIPOPROTEIN RECEPTOR-RELATED PROTEIN; LRP
ALPHA-2-MACROGLOBULIN RECEPTOR; A2MR
APOLIPOPROTEIN RECEPTOR; APR
APOLIPOPROTEIN E RECEPTOR; APOER
CD91
CED1, C. ELEGANS, HOMOLOG OF


HGNC Approved Gene Symbol: LRP1

Cytogenetic location: 12q13.3     Genomic coordinates (GRCh38): 12:57,128,483-57,213,361 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12q13.3 ?Keratosis pilaris atrophicans 604093 AR 3
Developmental dysplasia of the hip 3 620690 AD 3

TEXT

Description

LRP1 is synthesized as a 600-kD precursor transmembrane glycoprotein that is cleaved in trans-Golgi network by furin (136950) to generate a 515-kD alpha subunit and an 85-kD beta subunit. The alpha and beta subunits remain noncovalently associated during LRP1 transport to the cell membrane. LRP1 interacts with a broad range of secreted proteins and cell surface molecules and mediates their endocytosis and/or activates signaling pathways through multiple cytosolic adaptor and scaffold proteins. Phosphorylation of the LRP1 tail regulates ligand internalization and signal transduction (summary by Deane et al., 2004).


Cloning and Expression

Herz et al. (1988) cloned a cDNA for the low density lipoprotein receptor-related protein (LRP) by virtue of its close homology to the LDL receptor (606945). The 4,544-amino acid protein contains a single transmembrane segment. Northern blot analysis detected LRP1 mRNA in liver, brain, and lung. Kristensen et al. (1990) and Strickland et al. (1990) demonstrated that LRP is identical to alpha-2-macroglobulin (A2M; 103950) receptor (A2MR). Like mannose-6-phosphate receptor (147280), the A2MR/LRP molecule is probably bifunctional.

In the free-living nematode Caenorhabditis elegans, Yochem and Greenwald (1993) isolated and sequenced a gene more than 23 kb long that encodes a large integral membrane protein with a predicted structure similar to that of LRP of mammals. The 4,753-amino acid product predicted for the C. elegans gene shared a nearly identical number and arrangement of amino acid sequence motifs with human LRP, and several exons of the C. elegans LRP gene corresponded to exons of related parts of the human LRP gene.

Ranganathan et al. (2011) stated that the heavy chain of LRP1 contains 4 clusters of ligand-binding repeats. The light chain includes the transmembrane domain and cytoplasmic domain, which contains 2 NPxY motifs and 2 dileucine repeats that contribute to LRP1 endocytosis. Ranganathan et al. (2011) also purified a soluble form of LRP1 from human plasma.

Mark et al. (2022) stated that LRP1 is expressed in most human adult tissues, with high variability, elevation in fibroblasts, and no significant differences between males and females.


Mapping

Myklebost et al. (1989) mapped the gene for the LRP-related protein to 12q13-q14 by study of DNA from rodent-human cell hybrids and by in situ hybridization; the symbol APOER was used initially because of the putative APOE receptor function.

By pulsed field gel analysis, Forus et al. (1991) found that the APR and GLI genes are closely situated; probes for either gene hybridized to DNA fragments of molecular weight 300-400 kb. More detailed restriction analysis showed that the intergenic region was between 200 and 300 kb (Forus and Myklebost, 1992). Hilliker et al. (1992) confirmed the assignment to 12q13-q14 using both nonisotopic and isotopic in situ hybridization. Also by in situ hybridization, they assigned the corresponding locus to mouse chromosome 15. Binder et al. (2000) pointed out that gp96 and CD91 both map to the long arm of chromosome 12.


Gene Function

Herz et al. (1988) found that LRP showed strong calcium binding.

Kounnas et al. (1995) showed that LRP mediates the endocytosis and degradation of secreted amyloid precursor protein (APP; 104760), suggesting that a single metabolic pathway links 2 molecules implicated in the pathophysiology of Alzheimer disease (AD; 104300). Narita et al. (1997) showed that A2M, via LRP, mediates the clearance and degradation of APP-generated beta-amyloid (A-beta), the major component of amyloid plaques in AD.

Kang et al. (2000) demonstrated in vitro that LRP1 is required for the A2M-mediated clearance of A-beta 40 and 42 via a bona fide receptor-mediated cellular uptake mechanism. Analysis of postmortem human brain tissue showed that LRP expression normally declines with age, and that LRP expression in AD brains was significantly lower than in controls. Within the AD group, higher LRP levels were correlated with later age of onset of AD and death. Kang et al. (2000) concluded that reduced LRP expression is a contributing risk factor for AD, possibly by impeding the clearance of soluble beta-amyloid.

The heat-shock protein gp96 (TRA1; 191175) is an intracellular protein capable of chaperoning exogenous antigens from tumors or virus-infected cells to antigen-presenting cells for presentation through major histocompatibility complex (MHC) class I rather than class II molecules, thereby eliciting CD8 (186910)-positive T-cell responses. Using a mouse system, Binder et al. (2000) determined that the receptor for gp96 is CD91 (A2MR) and that A2M, a protein found in blood, inhibits gp96 binding to CD91. They proposed that CD91 acts as a sensor for necrotic cell death in tissues, leading to proinflammatory immune responses.

Basu et al. (2001) used fluorescence-labeled heat-shock proteins (HSPs) to show that not only GP96, but also HSP90 (HSPCA; 140571), HSP70 (see HSPA1A, 140550), and calreticulin (CALR; 109091) use CD91 as a common receptor. The ability of the cells to bind HSPs correlates with the proteasome- and TAP (170260)-dependent ability to re-present HSP-chaperoned peptides.

Forus et al. (1991) found that the APR and GLI (165220) genes are coamplified in a rhabdomyosarcoma cell line.

Smeijers et al. (2002) showed that murine Lrp1 is a cell surface receptor for Pseudomonas aeruginosa toxin A.

Wang et al. (2003) demonstrated that tissue plasminogen activator (tPA, or PLAT; 173370) upregulates MMP9 (120361) in cell culture and in vivo. MMP9 levels were lower in tPA knockout compared with wildtype mice after focal cerebral ischemia. In human cerebral microvascular endothelial cells, MMP9 was upregulated when recombinant tPA was added. RNA interference suggested that this response was mediated by LRP1, which avidly binds tPA and possesses signaling properties.

THBS1 (188060) or a peptide of the 19-amino acid active site in its heparin-binding domain signals focal adhesion disassembly through interaction with a cell surface form of calreticulin (CRT, or CALR; 109091). Using bovine aortic endothelial cells and wildtype and Lrp -/- mouse fibroblasts, Orr et al. (2003) showed that Lrp interacted with Crt and was required to mediate focal adhesion disassembly and downstream signaling for reorganization of focal adhesions. Binding of the LRP ligand RAP to purified human LRP inhibited interaction between recombinant human CRT and LRP.

Deane et al. (2004) found that wildtype A-beta 40 bound immobilized LRP with higher affinity than A-beta 42 or mutant A-beta 40 due to the lower beta sheet content of wildtype A-beta 40 compared with the other molecules. Lrp at mouse brain capillaries mediated clearance of wildtype A-beta 40 across the blood-brain barrier at a rate much higher than those for A-beta 42 and mutant A-beta 40. In primary human brain endothelial capillaries in culture, high concentrations of all A-beta species reduced LRP content via degradation in proteasomes. Loss of the LRP-binding protein Rap (LRPAP1; 104225) in Rap -/- mice reduced brain capillary clearance of all A-beta species. Expression of LRP was reduced in AD and Dutch-type cerebrovascular beta-amyloidosis (605714) brain tissue, suggesting that inadequate LRP-mediated A-beta clearance contributes to the formation of neurotoxic A-beta oligomers and progressive neuronal dysfunction.

The cysteine-rich extracellular domains (CRDs) of frizzled proteins (see FZ1, or FZD1; 603408) function as Wnt (see WNT3A; 606359) receptors. Using transfected HEK293 cells, Zilberberg et al. (2004) showed that LRP1 or a C-terminal fragment of LRP1 containing the fourth cluster of ligand-binding repeats, the transmembrane domain, and the cytoplasmic tail bound the CRD of human FZ1 and inhibited FZ1-dependent Wnt signaling. LRP1 did not mediate FZ1 internalization and degradation, but sequestered FZ1 and inhibited its formation of a functional Wnt signaling complex with LRP6 (603507).

Since BACE1 (604252) and APP interact and traffic with one another, and APP interacts with and traffics with LRP1, von Arnim et al. (2005) investigated interactions between BACE1 and LRP1. They found that BACE1 interacted with the light chain of LRP1 on the cell surface in association with lipid rafts. The BACE-LRP1 interaction led to increased LRP1 extracellular domain cleavage and subsequent release of the LRP1 intracellular domain from the membrane. Von Arnim et al. (2005) concluded that LRP1 is a BACE1 substrate.

Kinchen et al. (2005) showed that in C. elegans, CED1 (LRP1), CED6 (see 608165), and CED7 (see 601615) are required for actin reorganization around the apoptotic cell corpse, and that CED1 and CED6 colocalize with each other and with actin around the dead cell. Furthermore, Kinchen et al. (2005) found that the CED10 (RAC1; 602048) GTPase acts genetically downstream of these proteins to mediate corpse removal, functionally linking the 2 engulfment pathways and identifying the CED1, CED6, and CED7 signaling module as upstream regulators of Rac activation.

Using knockout mice, Liu et al. (2007) found that expression of Lrp1 was elevated following deletion of App, its homolog Aplp2 (104776), or components of the App-processing gamma-secretase complex (see 104311). Lrp1 expression was also elevated following inhibition of gamma-secretase activity. Elevated Lrp1 mRNA and protein was accompanied by increased catabolism of Apoe (107741) and cholesterol. Reporter gene assays and chromatin immunoprecipitation analysis revealed that the App intracellular domain (AICD), which is released along with A-beta by gamma-secretase activity, bound the Lrp1 promoter together with Fe65 (APBB1; 602709) and Tip60 (KAT5; 601409) and suppressed Lrp1 expression.

Gaultier et al. (2008) found that Schwann cells in injured rodent nerve exhibited increased expression of Lrp1. A soluble fragment of Lrp1 with an intact alpha chain (sLrp-alpha) was shed by Schwann cells in vitro and in the peripheral nervous system after injury. Injection of purified sLrp-alpha into mouse sciatic nerves prior to chronic constriction injury inhibited p38 Mapk (MAPK14; 600289) activation and decreased expression of Tnf-alpha (191160) and Il1-beta (147720) locally. sLrp-alpha also inhibited injury-induced spontaneous neuropathic pain and decreased inflammatory cytokine expression in the spinal dorsal horn, where neuropathic pain processing occurs. In cultured rat Schwann cells, astrocytes, and microglia, sLrp-alpha inhibited Tnf-alpha-induced activation of p38 Mapk and Erk/Mapk.

The cell surface receptor CED1 mediates apoptotic cell recognition by phagocytic cells, enabling cell corpse clearance in C. elegans. Chen et al. (2010) found that the C. elegans intracellular protein sorting complex, retromer, was required for cell corpse clearance by mediating the recycling of CED1. The mammalian retromer complex contains sorting nexins 1/2 (601272, 605929) (C. elegans homolog snx1) and 5/6 (605937, 606098) (C. elegans homolog snx6). Retromer was recruited to the surfaces of phagosomes containing cell corpses, and its loss of function caused defective cell corpse removal. The retromer probably acted through direct interaction with CED1 in the cell corpse recognition pathway. In the absence of retromer function, CED1 associated with lysosomes and failed to recycle from phagosomes and cytosol to the plasma membrane. Thus, Chen et al. (2010) concluded that retromer is an essential mediator of apoptotic cell clearance by regulating phagocytic receptor(s) during cell corpse engulfment.

Ranganathan et al. (2011) noted that previous work (Cao et al., 2006) had shown colocalization of LRP1 with integrin alpha-M (ITGAM; 120980)/beta-2 (ITGB2; 600065) at the trailing edge of migrating macrophages and that macrophage migration depended upon coordinated action of LRP1 and alpha-M/beta-2, as well as tissue plasminogen activator and its inhibitor, PAI1 (SERPINE1; 173360). Ranganathan et al. (2011) found that LRP1 specifically bound integrin alpha-M/beta-2, but not the homologous receptor integrin alpha-L (ITGAL; 153370)/beta-2. Activation of alpha-M/beta-2 by lipopolysaccharide (LPS) enhanced interaction between LRP1 and alpha-M/beta-2 in macrophages. Transfection experiments in HEK293 cells revealed that both the heavy and light chains of LRP1 contributed to alpha-M/beta-2 binding. Within the LRP1 heavy chain, binding was mediated primarily via ligand-binding motifs 2 and 4. Within alpha-M, the sequence EQLKKSKTL within the I domain was the major LRP1 recognition site. Exposure of alpha-M/beta-2-expressing HEK293 cells to soluble LRP1 inhibited cell attachment to fibrinogen (see 134820). Mouse macrophages lacking Lrp1 were deficient in alpha-M/beta-2 internalization upon LPS stimulation. Ranganathan et al. (2011) concluded that LRP1 has a role in macrophage migration and that it is critical for internalization of integrin alpha-M/beta-2.

Rauch et al. (2020) showed that LRP1 controls the endocytosis of tau (157140) and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Rauch et al. (2020) concluded that their results identified LRP1 as a key regulator of tau spread in the brain.


Molecular Genetics

Keratosis Pilaris Atrophicans

In 4 affected children from a consanguineous Pakistani family with keratosis pilaris atrophicans mapping to chromosome 12q (KPA; 604093), Klar et al. (2015) identified homozygosity for a missense mutation in the LRP1 gene (K1245R; 107770.0002). The mutation segregated fully with disease in the family and was not found in 200 Swedish or 200 Pakistani control chromosomes, in 900 in-house exomes, or in the dbSNP, EVS, ESP, or ExAC databases.

Developmental Dysplasia of the Hip 3

In 2 mother-daughter pairs from 2 Han Chinese families and in 7 unrelated Han Chinese children with developmental dysplasia of the hip (DDH3; 620690), Yan et al. (2022) identified heterozygosity for mutations in the LRP1 gene, including 7 missense variants and 3 splice site variants (see, e.g., 107770.0005-107770.0008). Functional analysis suggested that the variants cause LRP1 loss of function with a gene dosage effect, and analysis of a mouse model demonstrated premature fusion of the Y-shaped triradiate cartilage of the acetabulum, inhibiting bidirectional growth and resulting in the abnormally small acetabulum.

Association with Alzheimer Disease

The low density lipoprotein receptor-related protein gene was an attractive candidate for Alzheimer disease (AD) for several reasons. The multifunctional LRP had been shown to function as a receptor for the uptake of apolipoprotein E-containing lipoprotein particles by neurons. The apoE4 (107741) allele is strongly associated with an increased risk of late-onset familial Alzheimer disease and both late-onset and early-onset sporadic AD. The LRP receptor is prominently located in the soma regions and proximal processes of neurons. In a case-control study of 183 familial and sporadic AD patients and 118 controls, Lendon et al. (1997) found a moderate association (odds ratio = 1.57, p = 0.024) between AD and the 87-bp allele of a tetranucleotide repeat polymorphism located 5-prime to the LRP1 gene. Furthermore, Pericak-Vance et al. (1997) found in a genomic screen and follow-up analysis of 54 late-onset AD families, 4 regions potentially harboring AD genes; one of these regions, on chromosome 12, was located about 10 cM proximal of LRP1. Scott et al. (1998) examined 144 late-onset multiplex AD families, 436 sporadic AD cases, and 240 controls and found no evidence of linkage or association of LRP1 and AD. Their data indicated that genetic variation in the LRP1 gene is not a major risk factor in the etiology of Alzheimer disease.

Among 157 patients with late-onset AD (85 with a family history and 72 without a family history), Kang et al. (1997) found increased frequency of the C allele of a 766C-T polymorphism in exon 3 of the LRP1 gene compared to controls, although the C allele was common in controls. The authors suggested that the polymorphism, predicted to be silent, may be in linkage disequilibrium with a putative nearby AD susceptibility locus. Studies by Hollenbach et al. (1998) and Baum et al. (1998) also provided evidence of increased frequency of the 766C allele in patients with AD. McIlroy et al. (2001) found no association with the exon 3 polymorphism and development of AD.

Kang et al. (2000) noted that LRP and its ligands, APOE and alpha-2-macroglobulin, are all genetically associated with AD.

Bian et al. (2005) investigated the potential genetic contribution of 4 polymorphisms in LRP1 to AD in the Han Chinese population by studying 216 late-onset AD patients and 200 control subjects. The LRP1 CTCG haplotype (exon 3 T/C; intron 6 T/C, rs2306692; exon 22 T/C; intron 83 A/G, rs1800164) was overrepresented in the control group (p = 0.002). This difference was still statistically significant in the APOE4-negative subjects (p = 0.003), indicating that the CTCG haplotype of LRP1 may reduce the risk for late-onset AD.

Associations Pending Confirmation

For discussion of a possible association between variation in the LRP1 gene and abdominal aortic aneurysm, see AAA4 (614375).

For discussion of mutation in the LRP1 gene as a possible cause of intellectual disability, see 107770.0001.

For discussion of a possible association between a syndrome involving ascites, congenital heart defects, cardiopulmonary dysfunction, and dysmorphic features and variation in the LRP1 gene, see 107770.0003.


Animal Model

Boucher et al. (2003) developed tissue-specific knockout mice that lacked Lrp1 only in vascular smooth muscle cells. To increase susceptibility to spontaneous atherosclerotic lesion development, these animals were crossed to LDL receptor (Ldlr; 606945) knockout mice to generate Ldlr-/smooth muscle Lrp- mice. The presence or absence of Lrp1 expression in smooth muscle cells had no effect on plasma cholesterol or triglyceride levels in mice on normal chow or an atherogenic high-cholesterol diet. However, aortas from smooth muscle Lrp- mice were consistently distended and dilated. This difference increased over time and was accompanied by thickening of the aortic wall, pronounced atherosclerosis, and aneurysm formation. Boucher et al. (2003) showed that Lrp1 forms a complex with the PDGF receptor (see PDGFR1, 173410). Inactivation of Lrp1 in vascular smooth muscle cells of mice caused PDGFR overexpression and abnormal activation of PDGFR signaling, resulting in disruption of the elastic layer, smooth muscle cell proliferation, aneurysm formation, and marked susceptibility to cholesterol-induced atherosclerosis. The development of these abnormalities was reduced by treatment with Gleevec, an inhibitor of PDGF signaling. Thus, Boucher et al. (2003) concluded that LRP1 has a pivotal role in protecting vascular wall integrity and preventing atherosclerosis by controlling PDGFR activation.

May et al. (2004) found that mice with targeted disruption of the Lrp1 gene in differentiated postmitotic neurons demonstrated hyperactivity and constant tremor, and later developed dystonic posturing with increased thoracic kyphosis, waddling gait, and hindlimb weakness, suggesting motoneuronal disinhibition or motor excitation. The transgenic mice died prematurely at about 9 months of age. Brain morphology was normal with no major neuronal loss, suggesting a functional abnormality in neurotransmission. In vitro, LRP1 coimmunoprecipitated and colocalized with the postsynaptic protein PSD95 (602887) and the N-methyl-D-aspartate (NMDA) receptor subunits NR2A (138253) and NR2B (138252). Treatment of neurons with NMDA reduced the interaction of Lrp1 and Psd95. May et al. (2004) concluded that LRP1 plays a role in behavior and motor function by regulating postsynaptic signaling mechanisms through interaction with NMDA receptors.

Hofmann et al. (2007) generated mice with adipocyte-specific inactivation of LRP1 and observed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. In addition, the mutant mice were resistant to dietary fat-induced obesity and glucose intolerance. Hofmann et al. (2007) concluded that LRP1 is a critical regulator of adipocyte energy homeostasis.

Using the CRISPR/Cas9 genome editing system, Yan et al. (2022) established a knockin mouse line (KI) with an Lrp1 R1783W substitution, the same LRP1 variant that they had identified in a mother and daughter with developmental dysplasia of the hip (DDH3; see 107770.0005). They also generated heterozygous Lrp1 knockout (KO) mice (homozygous KO mice were not obtained). Western blot and protein mass spectrometry analyses showed significant reductions in expression levels of Lrp1 in the mutants compared to wildtype mice, with heterozygous KI mice having expression levels of Lrp1 between those of wildtype and homozygous KI mice, and KI homozygotes having levels similar to those of the KO heterozygotes. Micro-CT analysis of the hip joint showed a dramatic reduction of the acetabular volume in KI homozygotes and KI and KO heterozygotes compared to wildtype mice, with defective coverage of the femoral head. Acetabular volumes of the mutant mice were consistent with the Lrp1 expression levels, with KI heterozygotes having a smaller acetabulum than wildtype mice, but larger than KI homozygotes. Histologic analysis of hip joint sections revealed that the Y-shaped triradiate acetabular cartilage had closed completely before 6 weeks in KI and KO mice, whereas it closed after 8 weeks in wildtype mice. The authors suggested that the premature fusion associated with Lrp1 deficiency inhibits bidirectional growth of the triradiate cartilage, resulting in an abnormally small acetabulum. Proteome experiments showed a significant reduction in collagen expression in the hip joints of both heterozygous and homozygous KI mice compared to wildtype littermates, and autophagy proteins were significantly increased, with both presenting a dosage effect. In addition, Lrp1 deficiency caused a significant decrease of chondrogenic ability in vitro. During the chondrogenic induction of mouse bone marrow stem cells and ATDC5 (an inducible chondrogenic cell line), Lrp1 deficiency caused decreased autophagy levels with significant beta-catenin (CTNNB1; 116806) upregulation and suppression of chondrocyte marker genes. The expression of chondrocyte markers was rescued by PNU-74654 (a beta-catenin antagonist) in an shRNA-Lrp1-expressed ATDC5 cell. The authors concluded that LRP1 plays a critical role in the etiology and pathogenesis of DDH.


ALLELIC VARIANTS ( 8 Selected Examples):

.0001 VARIANT OF UNKNOWN SIGNIFICANCE

LRP1, HIS3258GLN
  
RCV000033099...

This variant is classified as a variant of unknown significance because its contribution to intellectual disability has not been confirmed.

In a boy who developed seizures and developmental stagnation at age 22 months and ultimately had severe intellectual disability with an IQ of 34, stereotypic behavior, high pain threshold, and sleep disturbances with a normal brain MRI and no dysmorphic features, de Ligt et al. (2012) identified a de novo heterozygous 9774C-G transversion resulting in a his3258-to-gln (H3258Q) substitution.


.0002 KERATOSIS PILARIS ATROPHICANS (1 family)

LRP1, LYS1245ARG
  
RCV000119304...

In 4 affected children from a consanguineous Pakistani family with a mixed type of keratosis pilaris atrophicans (KPA; 604093), Klar et al. (2015) identified homozygosity for a c.3734A-G transition (c.3734A-G, NM_002332.2) in exon 23 of the LRP1 gene, resulting in a lys1245-to-arg (K1245R) substitution at a highly conserved residue within the sixth epidermal growth factor (EGF)-like domain. The mutation segregated fully with disease in the family and was not found in 200 Swedish or 200 Pakistani control chromosomes, in 900 in-house exomes, or in the dbSNP, EVS, ESP, or ExAC databases. Analysis of mRNA from patient fibroblast cultures showed a 5-fold reduction in LRP1 mRNA compared to age-matched controls; immunostaining and fluorescence confocal microscopy confirmed significantly reduced LRP1 levels in patient cells compared to controls. In addition, there was a marked reduction in cellular uptake of the known LRP1 ligand A2M (103950) in patient fibroblasts compared to controls, and intracellular A2M levels were reduced beyond what would be expected from the LRP1 levels (p = 0.0017) compared to controls, suggesting that binding properties of LRP1 to A2M were altered in the patients.


.0003 VARIANT OF UNKNOWN SIGNIFICANCE

LRP1, CYS3807SER
   RCV003147750

This variant is classified as a variant of unknown significance because its contribution to a syndrome involving ascites, congenital heart defects, cardiopulmonary dysfunction, and dysmorphic features has not been confirmed.

In a sister and brother with ascites, congenital heart defects, cardiopulmonary dysfunction, and dysmorphic features, Mark et al. (2022) performed rapid genome sequencing and identified compound heterozygosity for 2 missense mutations in the LRP1 gene: a c.11420G-C transversion (SCV002569952), resulting in a cys3807-to-ser (C3807S) substitution, and a c.12407T-G transversion, resulting in a val4136-to-gly (V4136G; 107770.0004) substitution, both at highly conserved residues. Their unaffected parents were heterozygous for the variants, which were not found in the gnomAD database. Both sibs were born with severe respiratory distress requiring intubation and mechanical ventilation. Other overlapping features included prenatal detection of polyhydramnios, cerebral ventriculomegaly, and fetal ascites, and postnatal observation of hypotonia, large anterior fontanel, hypertelorism, prominent under-orbital creases, corneal clouding, low-set ears, large patent ductus arteriosus, coarctation of the aorta, massive ascites, cerebral ventriculomegaly, and paddle-shaped fingertips and toes. Additional features in the sister included cleft soft palate, upslanting palpebral fissures, hypoplastic aortic valve, patent foramen ovale, dysplastic pulmonary valve, and single palmar creases. She developed pulmonary hypertension and severe hypertrophic cardiomyopathy. She had stable hepatomegaly, with clinical resolution of ascites over time. Ophthalmologic assessment revealed glaucoma, and she had enlarged pupils and irises. Additional features in the brother included large size for gestational age, single umbilical artery, large ventricular septal defect, undescended and nonpalpable testes, and no spontaneous movement. He required paracentesis of ascites in the delivery room to allow for lung expansion, and had bilateral hydronephrosis with proximal hydroureter. The sister died at 5 months of age due to cardiac arrest; the brother, who was hypotonic, unresponsive, and oliguric after birth was extubated on day 2 of life and expired shortly thereafter. The authors stated that mouse-model phenotypes present in Lrp1 knockouts aligned with features observed in the affected sibs.


.0004 VARIANT OF UNKNOWN SIGNIFICANCE

LRP1, VAL4136GLY
   RCV003147749

For discussion of the c.12407T-G transversion (SCV002569951) in the LRP1 gene, resulting in a val4136-to-gly (V4136G) substitution, that was found in compound heterozygous state in 2 sibs with ascites, congenital heart defects, cardiopulmonary dysfunction, and dysmorphic features by Mark et al. (2022), see 107770.0003.


.0005 DEVELOPMENTAL DYSPLASIA OF THE HIP 3

LRP1, ARG1783TRP
   RCV003493368

In a 2-year-old Han Chinese girl (patient 2621) with bilateral developmental dysplasia of the hip (DDH3; 620690), Yan et al. (2022) identified heterozygosity for a c.5347C-T transition (c.5347C-T, NM_002332) in exon 32 of the LRP1 gene, resulting in an arg1783-to-trp (R1783W) substitution at a highly conserved residue. Her affected mother was also heterozygous for the mutation, which was present at low minor allele frequency (MAF 0.0001) in the East Asian population of the ExAC database and at very low MAF (2.785 x 10(-5)) in the gnomAD database; the variant was not found in the 1000 Genomes Project or ESP6500 databases. Using the CRISPR/Cas9 genome editing system, the authors generated a knockin mouse line (KI) with an Lrp1 R1783W substitution. Western blot and protein mass spectrometry analyses showed that heterozygous KI mice had expression levels of Lrp1 that were between those of wildtype and homozygous KI mice, and that the homozygous KI levels were similar to those of mice with heterozygous knockout of Lrp1. In addition, acetabular volumes of the mutant mice were consistent with the Lrp1 expression levels, with KI heterozygotes having a smaller acetabulum than wildtype mice, but larger than KI homozygotes. The authors suggested that the R1783 mutant causes loss of function with a gene dosage effect.


.0006 DEVELOPMENTAL DYSPLASIA OF THE HIP 3

LRP1, THR2129LYS
   RCV003493369

In a 1.5-year-old Han Chinese girl (patient 2726) with unilateral developmental dysplasia of the hip (DDH3; 620690), Yan et al. (2022) identified heterozygosity for a c.6386C-A transversion (c.6386C-A, NM_002332) in exon 40 of the LRP1 gene, resulting in a thr2129-to-lys (T2129K) substitution at a highly conserved residue. Her affected mother was also heterozygous for the mutation, which was present at low minor allele frequency (MAF 0.0006) in the East Asian population of the ExAC database and at very low MAF (2.784 x 10(-5)) in the gnomAD database; the variant was not found in the 1000 Genomes Project or ESP6500 databases.


.0007 DEVELOPMENTAL DYSPLASIA OF THE HIP 3

LRP1, PRO224ALA
   RCV003493370

In a 5-month-old Han Chinese infant (patient 3193) with unilateral developmental dysplasia of the hip (DDH3; 620690), Yan et al. (2022) identified heterozygosity for a c.670C-G transversion (c.670C-G, NM_002332) in exon 6 of the LRP1 gene, resulting in a pro224-to-ala (P224A) substitution. The variant was not found in the East Asian population of the ExAC database or in the gnomAD, 1000 Genomes Project, or ESP6500 databases; familial segregation was not reported.


.0008 DEVELOPMENTAL DYSPLASIA OF THE HIP 3

LRP1, IVS17AS, C-A, -4
   RCV003493371

In an 8-month-old Han Chinese infant (patient 3196) with unilateral developmental dysplasia of the hip (DDH3; 620690), Yan et al. (2022) identified heterozygosity for a splice site mutation in intron 17 of the LRP1 gene (c.2798-4C-A, NM_002332). The variant was present at low minor allele frequency (MAF 0.0001) in the East Asian population of the ExAC database and at very low MAF (2.023 x 10(-5)) in the gnomAD database; the variant was not found in the 1000 Genomes Project or ESP6500 databases. Familial segregation was not reported.


See Also:

REFERENCES

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  11. Forus, A., Maelandsmo, G. M., Fodstad, Y., Myklebost, O. The genes for the alpha-2-macroglobulin receptor/LDL receptor-related protein and GLI are located within a chromosomal segment of about 300 kilobases and are coamplified in a rhabdomyosarcoma cell line. (Abstract) Cytogenet. Cell Genet. 58: 1977 only, 1991.

  12. Forus, A., Myklebost, O. A physical map of a 1.3-Mb region on the long arm of chromosome 12, spanning the GLI and LRP loci. Genomics 14: 117-120, 1992. [PubMed: 1427818, related citations] [Full Text]

  13. Gaultier, A., Arandjelovic, S., Li, X., Janes, J., Dragojlovic, N., Zhou, G. P., Dolkas, J., Myers, R. R., Gonias, S. L., Campana, W. M. A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents. J. Clin. Invest. 118: 161-172, 2008. [PubMed: 18060043, images, related citations] [Full Text]

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  18. Kang, D. E., Pietrzik, C. U., Baum, L., Chevallier, N., Merriam, D. E., Kounnas, M. Z., Wagner, S. L., Troncoso, J. C., Kawas, C. H., Katzman, R., Koo, E. H. Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway. J. Clin. Invest. 106: 1159-1166, 2000. [PubMed: 11067868, images, related citations] [Full Text]

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  20. Kinchen, J. M., Cabello, J., Klingele, D., Wong, K., Feichtinger, R., Schnabel, H., Schnabel, R., Hengartner, M. O. Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans. Nature 434: 93-99, 2005. [PubMed: 15744306, related citations] [Full Text]

  21. Klar, J., Schuster, J., Khan, T. N., Jameel, M., Mabert, K., Forsberg, L., Baig, S. A., Baig, S. M., Dahl, N. Whole exome sequencing identifies LRP1 as a pathogenic gene in autosomal recessive keratosis pilaris atrophicans. J. Med. Genet. 52: 599-606, 2015. [PubMed: 26142438, related citations] [Full Text]

  22. Kounnas, M. Z., Moir, R. D., Rebeck, G. W., Bush, A. I., Argraves, W. S., Tanzi, R. E., Hyman, B. T., Strickland, D. K. LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Cell 82: 331-340, 1995. [PubMed: 7543026, related citations] [Full Text]

  23. Kristensen, T., Moestrup, S. K., Gliemann, J., Bendtsen, L., Sand, O., Sottrup-Jensen, L. Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the alpha-2-macroglobulin receptor. FEBS Lett. 276: 151-155, 1990. [PubMed: 1702392, related citations] [Full Text]

  24. Lendon, C. L., Talbot, C. J., Craddock, N. J., Han, S. W., Wragg, M., Morris, J. C., Goate, A. M. Genetic association studies between dementia of the Alzheimer's type and three receptors for apolipoprotein E in a Caucasian population. Neurosci. Lett. 222: 187-190, 1997. [PubMed: 9148246, related citations] [Full Text]

  25. Liu, Q., Zerbinatti, C. V., Zhang, J., Hoe, H.-S., Wang, B., Cole, S. L., Herz, J., Muglia, L., Bu, G. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56: 66-78, 2007. [PubMed: 17920016, images, related citations] [Full Text]

  26. Mark, P. R., Murray, S. A., Yang, T., Eby, A., Lai, A., Lu, D., Zieba, J., Rajasekaran, S., VanSickle, E. A., Rossetti, L. Z., Guidugli, L., Watkins, K., Wright, M. S., Bupp, C. P., Prokop, J. W. Autosomal recessive LRP1-related syndrome featuring cardiopulmonary dysfunction, bone dysmorphology, and corneal clouding. Cold Spring Harbor Molec. Case Stud. 8: a006169, 2022. [PubMed: 36307211, images, related citations] [Full Text]

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  28. McIlroy, S. P., Dynan, K. B., Vahidassr, D. J., Lawson, J. T., Patterson, C. C., Passmore, P. Common polymorphisms in LRP and A2M do not affect genetic risk for Alzheimer disease in Northern Ireland. Am. J. Med. Genet. 105: 502-506, 2001. [PubMed: 11496365, related citations] [Full Text]

  29. Myklebost, O., Arheden, K., Rogne, S., Geurts van Kessel, A., Mandahl, N., Herz, J., Stanley, K., Heim, S., Mitelman, F. The gene for the human putative apoE receptor is on chromosome 12 in the segment q13-14. Genomics 5: 65-69, 1989. [PubMed: 2548950, related citations] [Full Text]

  30. Narita, M., Holtzman, D. M., Schwartz, A. L., Bu, G. Alpha-2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein. J. Neurochem. 69: 1904-1911, 1997. [PubMed: 9349534, related citations] [Full Text]

  31. Orr, A. W., Pedraza, C. E., Pallero, M. A., Elzie, C. A., Goicoechea, S., Strickland, D. K., Murphy-Ullrich, J. E. Low density lipoprotein receptor-related protein is a calreticulin coreceptor that signals focal adhesion disassembly. J. Cell Biol. 161: 1179-1189, 2003. Note: Erratum: J. Cell Biol. 162: 521 only, 2003. [PubMed: 12821648, images, related citations] [Full Text]

  32. Pericak-Vance, M. A., Bass, M. P., Yamaoka, L. H., Gaskell, P. C., Scott, W. K., Terwedow, H. A., Menold, M. M., Conneally, P. M., Small, G. W., Vance, J. M., Saunders, A. M., Roses, A. D., Haines, J. L. Complete genomic screen in late-onset familial Alzheimer disease: evidence for a new locus on chromosome 12. JAMA 278: 1237-1241, 1997. [PubMed: 9333264, related citations]

  33. Ranganathan, S., Cao, C., Catania, J., Migliorini, M., Zhang, L., Strickland, D. K. Molecular basis for the interaction of low density lipoprotein receptor-related protein 1 (LRP1) with integrin alpha-M/beta-2: identification of binding sites within alpha-M/beta-2 for LRP1. J. Biol. Chem. 286: 30535-30541, 2011. [PubMed: 21676865, images, related citations] [Full Text]

  34. Rauch, J. N., Luna, G., Guzman, E., Audouard, M., Challis, C., Sibih, YE., Leshuk, C., Hernandez, I., Wegmann, S., Hyman, B. T., Gradinaru, V., Kampmann, M., Kosik, K. S. LRP1 is a master regulator of tau uptake and spread. Nature 580: 381-385, 2020. [PubMed: 32296178, images, related citations] [Full Text]

  35. Scott, W. K., Yamaoka, L. H., Bass, M. P., Gaskell, P. C., Conneally, P. M., Small, G. W., Farrer, L. A., Auerbach, S. A., Saunders, A. M., Roses, A. D., Haines, J. L., Pericak-Vance, M. A. No genetic association between the LRP receptor and sporadic or late-onset familial Alzheimer disease. Neurogenetics 1: 179-183, 1998. [PubMed: 10737120, related citations] [Full Text]

  36. Smeijers, L., Willems, S., Lauwers, A., Thiry, E., van Leuven, F., Roebroek, A. J. M. Functional expression of murine LRP1 requires correction of Lrp1 cDNA sequences. Biochim. Biophys. Acta 1577: 155-158, 2002. [PubMed: 12151109, related citations] [Full Text]

  37. Strickland, D. K., Ashcom, J. D., Williams, S., Burgess, W. H., Migliorini, M., Argraves, W. S. Sequence identity between the alpha-2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J. Biol. Chem. 265: 17401-17404, 1990. [PubMed: 1698775, related citations]

  38. von Arnim, C. A. F., Kinoshita, A., Peltan, I. D., Tangredi, M. M., Herl, L., Lee, B. M., Spoelgen, R., Hshieh, T. T., Ranganathan, S., Battey, F. D., Liu, C.-X., Baeskai, B. J., Sever, S., Irizarry, M. C., Strickland, D. K., Hyman, B. T. The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. J. Biol. Chem. 280: 17777-17785, 2005. [PubMed: 15749709, related citations] [Full Text]

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  40. Yan, W., Zheng, L., Xu, X., Hao, Z., Zhang, Y., Lu, J., Sun, Z., Dai, J., Shi, D., Guo, B., Jiang, Q. Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy. Proc. Nat. Acad. Sci. 119: e2203557119, 2022. [PubMed: 36067312, images, related citations] [Full Text]

  41. Yochem, J., Greenwald, I. A gene for a low density lipoprotein receptor-related protein in the nematode Caenorhabditis elegans. Proc. Nat. Acad. Sci. 90: 4572-4576, 1993. [PubMed: 8506301, related citations] [Full Text]

  42. Zilberberg, A., Yaniv, A., Gazit, A. The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway. J. Biol. Chem. 279: 17535-17542, 2004. [PubMed: 14739301, related citations] [Full Text]


Marla J. F. O'Neill - updated : 01/26/2024
Marla J. F. O'Neill - updated : 01/03/2023
Ada Hamosh - updated : 08/14/2020
Marla J. F. O'Neill - updated : 11/11/2016
Patricia A. Hartz - updated : 6/11/2013
Ada Hamosh - updated : 2/13/2013
Marla J. F. O'Neill - updated : 12/2/2011
Patricia A. Hartz - updated : 4/19/2011
Ada Hamosh - updated : 4/22/2010
Patricia A. Hartz - updated : 3/13/2008
Marla J. F. O'Neill - updated : 1/17/2008
John Logan Black, III - updated : 7/12/2006
Ada Hamosh - updated : 2/1/2006
Patricia A. Hartz - updated : 11/9/2005
Cassandra L. Kniffin - updated : 11/15/2004
Ada Hamosh - updated : 9/23/2003
Cassandra L. Kniffin - updated : 6/3/2003
Ada Hamosh - updated : 4/22/2003
Paul J. Converse - updated : 10/29/2001
Paul J. Converse - updated : 9/15/2000
Victor A. McKusick - updated : 5/5/1998
Creation Date:
Victor A. McKusick : 11/23/1988
carol : 03/04/2024
alopez : 01/26/2024
alopez : 01/03/2023
alopez : 08/14/2020
alopez : 08/20/2018
carol : 11/14/2016
alopez : 11/11/2016
mcolton : 04/01/2014
tpirozzi : 7/9/2013
mgross : 6/12/2013
mgross : 6/11/2013
mgross : 6/11/2013
mgross : 6/11/2013
mgross : 6/11/2013
carol : 5/29/2013
carol : 2/13/2013
carol : 2/13/2013
carol : 12/6/2011
terry : 12/2/2011
mgross : 6/3/2011
terry : 4/19/2011
alopez : 4/26/2010
terry : 4/22/2010
terry : 6/3/2009
mgross : 3/17/2008
terry : 3/13/2008
wwang : 2/18/2008
terry : 1/17/2008
carol : 7/12/2006
terry : 7/12/2006
alopez : 2/2/2006
terry : 2/1/2006
mgross : 12/2/2005
terry : 11/9/2005
tkritzer : 11/29/2004
ckniffin : 11/15/2004
alopez : 10/16/2003
alopez : 9/23/2003
terry : 7/31/2003
carol : 6/6/2003
ckniffin : 6/3/2003
ckniffin : 6/3/2003
alopez : 4/22/2003
alopez : 4/22/2003
terry : 4/22/2003
ckniffin : 6/5/2002
cwells : 10/29/2001
cwells : 10/29/2001
mgross : 9/15/2000
psherman : 10/14/1998
dholmes : 7/2/1998
carol : 5/14/1998
carol : 5/12/1998
terry : 5/5/1998
carol : 8/3/1994
warfield : 3/11/1994
carol : 6/17/1993
carol : 9/22/1992
carol : 6/1/1992
supermim : 3/16/1992

* 107770

LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 1; LRP1


Alternative titles; symbols

LIPOPROTEIN RECEPTOR-RELATED PROTEIN; LRP
ALPHA-2-MACROGLOBULIN RECEPTOR; A2MR
APOLIPOPROTEIN RECEPTOR; APR
APOLIPOPROTEIN E RECEPTOR; APOER
CD91
CED1, C. ELEGANS, HOMOLOG OF


HGNC Approved Gene Symbol: LRP1

SNOMEDCT: 400059005;  


Cytogenetic location: 12q13.3     Genomic coordinates (GRCh38): 12:57,128,483-57,213,361 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12q13.3 ?Keratosis pilaris atrophicans 604093 Autosomal recessive 3
Developmental dysplasia of the hip 3 620690 Autosomal dominant 3

TEXT

Description

LRP1 is synthesized as a 600-kD precursor transmembrane glycoprotein that is cleaved in trans-Golgi network by furin (136950) to generate a 515-kD alpha subunit and an 85-kD beta subunit. The alpha and beta subunits remain noncovalently associated during LRP1 transport to the cell membrane. LRP1 interacts with a broad range of secreted proteins and cell surface molecules and mediates their endocytosis and/or activates signaling pathways through multiple cytosolic adaptor and scaffold proteins. Phosphorylation of the LRP1 tail regulates ligand internalization and signal transduction (summary by Deane et al., 2004).


Cloning and Expression

Herz et al. (1988) cloned a cDNA for the low density lipoprotein receptor-related protein (LRP) by virtue of its close homology to the LDL receptor (606945). The 4,544-amino acid protein contains a single transmembrane segment. Northern blot analysis detected LRP1 mRNA in liver, brain, and lung. Kristensen et al. (1990) and Strickland et al. (1990) demonstrated that LRP is identical to alpha-2-macroglobulin (A2M; 103950) receptor (A2MR). Like mannose-6-phosphate receptor (147280), the A2MR/LRP molecule is probably bifunctional.

In the free-living nematode Caenorhabditis elegans, Yochem and Greenwald (1993) isolated and sequenced a gene more than 23 kb long that encodes a large integral membrane protein with a predicted structure similar to that of LRP of mammals. The 4,753-amino acid product predicted for the C. elegans gene shared a nearly identical number and arrangement of amino acid sequence motifs with human LRP, and several exons of the C. elegans LRP gene corresponded to exons of related parts of the human LRP gene.

Ranganathan et al. (2011) stated that the heavy chain of LRP1 contains 4 clusters of ligand-binding repeats. The light chain includes the transmembrane domain and cytoplasmic domain, which contains 2 NPxY motifs and 2 dileucine repeats that contribute to LRP1 endocytosis. Ranganathan et al. (2011) also purified a soluble form of LRP1 from human plasma.

Mark et al. (2022) stated that LRP1 is expressed in most human adult tissues, with high variability, elevation in fibroblasts, and no significant differences between males and females.


Mapping

Myklebost et al. (1989) mapped the gene for the LRP-related protein to 12q13-q14 by study of DNA from rodent-human cell hybrids and by in situ hybridization; the symbol APOER was used initially because of the putative APOE receptor function.

By pulsed field gel analysis, Forus et al. (1991) found that the APR and GLI genes are closely situated; probes for either gene hybridized to DNA fragments of molecular weight 300-400 kb. More detailed restriction analysis showed that the intergenic region was between 200 and 300 kb (Forus and Myklebost, 1992). Hilliker et al. (1992) confirmed the assignment to 12q13-q14 using both nonisotopic and isotopic in situ hybridization. Also by in situ hybridization, they assigned the corresponding locus to mouse chromosome 15. Binder et al. (2000) pointed out that gp96 and CD91 both map to the long arm of chromosome 12.


Gene Function

Herz et al. (1988) found that LRP showed strong calcium binding.

Kounnas et al. (1995) showed that LRP mediates the endocytosis and degradation of secreted amyloid precursor protein (APP; 104760), suggesting that a single metabolic pathway links 2 molecules implicated in the pathophysiology of Alzheimer disease (AD; 104300). Narita et al. (1997) showed that A2M, via LRP, mediates the clearance and degradation of APP-generated beta-amyloid (A-beta), the major component of amyloid plaques in AD.

Kang et al. (2000) demonstrated in vitro that LRP1 is required for the A2M-mediated clearance of A-beta 40 and 42 via a bona fide receptor-mediated cellular uptake mechanism. Analysis of postmortem human brain tissue showed that LRP expression normally declines with age, and that LRP expression in AD brains was significantly lower than in controls. Within the AD group, higher LRP levels were correlated with later age of onset of AD and death. Kang et al. (2000) concluded that reduced LRP expression is a contributing risk factor for AD, possibly by impeding the clearance of soluble beta-amyloid.

The heat-shock protein gp96 (TRA1; 191175) is an intracellular protein capable of chaperoning exogenous antigens from tumors or virus-infected cells to antigen-presenting cells for presentation through major histocompatibility complex (MHC) class I rather than class II molecules, thereby eliciting CD8 (186910)-positive T-cell responses. Using a mouse system, Binder et al. (2000) determined that the receptor for gp96 is CD91 (A2MR) and that A2M, a protein found in blood, inhibits gp96 binding to CD91. They proposed that CD91 acts as a sensor for necrotic cell death in tissues, leading to proinflammatory immune responses.

Basu et al. (2001) used fluorescence-labeled heat-shock proteins (HSPs) to show that not only GP96, but also HSP90 (HSPCA; 140571), HSP70 (see HSPA1A, 140550), and calreticulin (CALR; 109091) use CD91 as a common receptor. The ability of the cells to bind HSPs correlates with the proteasome- and TAP (170260)-dependent ability to re-present HSP-chaperoned peptides.

Forus et al. (1991) found that the APR and GLI (165220) genes are coamplified in a rhabdomyosarcoma cell line.

Smeijers et al. (2002) showed that murine Lrp1 is a cell surface receptor for Pseudomonas aeruginosa toxin A.

Wang et al. (2003) demonstrated that tissue plasminogen activator (tPA, or PLAT; 173370) upregulates MMP9 (120361) in cell culture and in vivo. MMP9 levels were lower in tPA knockout compared with wildtype mice after focal cerebral ischemia. In human cerebral microvascular endothelial cells, MMP9 was upregulated when recombinant tPA was added. RNA interference suggested that this response was mediated by LRP1, which avidly binds tPA and possesses signaling properties.

THBS1 (188060) or a peptide of the 19-amino acid active site in its heparin-binding domain signals focal adhesion disassembly through interaction with a cell surface form of calreticulin (CRT, or CALR; 109091). Using bovine aortic endothelial cells and wildtype and Lrp -/- mouse fibroblasts, Orr et al. (2003) showed that Lrp interacted with Crt and was required to mediate focal adhesion disassembly and downstream signaling for reorganization of focal adhesions. Binding of the LRP ligand RAP to purified human LRP inhibited interaction between recombinant human CRT and LRP.

Deane et al. (2004) found that wildtype A-beta 40 bound immobilized LRP with higher affinity than A-beta 42 or mutant A-beta 40 due to the lower beta sheet content of wildtype A-beta 40 compared with the other molecules. Lrp at mouse brain capillaries mediated clearance of wildtype A-beta 40 across the blood-brain barrier at a rate much higher than those for A-beta 42 and mutant A-beta 40. In primary human brain endothelial capillaries in culture, high concentrations of all A-beta species reduced LRP content via degradation in proteasomes. Loss of the LRP-binding protein Rap (LRPAP1; 104225) in Rap -/- mice reduced brain capillary clearance of all A-beta species. Expression of LRP was reduced in AD and Dutch-type cerebrovascular beta-amyloidosis (605714) brain tissue, suggesting that inadequate LRP-mediated A-beta clearance contributes to the formation of neurotoxic A-beta oligomers and progressive neuronal dysfunction.

The cysteine-rich extracellular domains (CRDs) of frizzled proteins (see FZ1, or FZD1; 603408) function as Wnt (see WNT3A; 606359) receptors. Using transfected HEK293 cells, Zilberberg et al. (2004) showed that LRP1 or a C-terminal fragment of LRP1 containing the fourth cluster of ligand-binding repeats, the transmembrane domain, and the cytoplasmic tail bound the CRD of human FZ1 and inhibited FZ1-dependent Wnt signaling. LRP1 did not mediate FZ1 internalization and degradation, but sequestered FZ1 and inhibited its formation of a functional Wnt signaling complex with LRP6 (603507).

Since BACE1 (604252) and APP interact and traffic with one another, and APP interacts with and traffics with LRP1, von Arnim et al. (2005) investigated interactions between BACE1 and LRP1. They found that BACE1 interacted with the light chain of LRP1 on the cell surface in association with lipid rafts. The BACE-LRP1 interaction led to increased LRP1 extracellular domain cleavage and subsequent release of the LRP1 intracellular domain from the membrane. Von Arnim et al. (2005) concluded that LRP1 is a BACE1 substrate.

Kinchen et al. (2005) showed that in C. elegans, CED1 (LRP1), CED6 (see 608165), and CED7 (see 601615) are required for actin reorganization around the apoptotic cell corpse, and that CED1 and CED6 colocalize with each other and with actin around the dead cell. Furthermore, Kinchen et al. (2005) found that the CED10 (RAC1; 602048) GTPase acts genetically downstream of these proteins to mediate corpse removal, functionally linking the 2 engulfment pathways and identifying the CED1, CED6, and CED7 signaling module as upstream regulators of Rac activation.

Using knockout mice, Liu et al. (2007) found that expression of Lrp1 was elevated following deletion of App, its homolog Aplp2 (104776), or components of the App-processing gamma-secretase complex (see 104311). Lrp1 expression was also elevated following inhibition of gamma-secretase activity. Elevated Lrp1 mRNA and protein was accompanied by increased catabolism of Apoe (107741) and cholesterol. Reporter gene assays and chromatin immunoprecipitation analysis revealed that the App intracellular domain (AICD), which is released along with A-beta by gamma-secretase activity, bound the Lrp1 promoter together with Fe65 (APBB1; 602709) and Tip60 (KAT5; 601409) and suppressed Lrp1 expression.

Gaultier et al. (2008) found that Schwann cells in injured rodent nerve exhibited increased expression of Lrp1. A soluble fragment of Lrp1 with an intact alpha chain (sLrp-alpha) was shed by Schwann cells in vitro and in the peripheral nervous system after injury. Injection of purified sLrp-alpha into mouse sciatic nerves prior to chronic constriction injury inhibited p38 Mapk (MAPK14; 600289) activation and decreased expression of Tnf-alpha (191160) and Il1-beta (147720) locally. sLrp-alpha also inhibited injury-induced spontaneous neuropathic pain and decreased inflammatory cytokine expression in the spinal dorsal horn, where neuropathic pain processing occurs. In cultured rat Schwann cells, astrocytes, and microglia, sLrp-alpha inhibited Tnf-alpha-induced activation of p38 Mapk and Erk/Mapk.

The cell surface receptor CED1 mediates apoptotic cell recognition by phagocytic cells, enabling cell corpse clearance in C. elegans. Chen et al. (2010) found that the C. elegans intracellular protein sorting complex, retromer, was required for cell corpse clearance by mediating the recycling of CED1. The mammalian retromer complex contains sorting nexins 1/2 (601272, 605929) (C. elegans homolog snx1) and 5/6 (605937, 606098) (C. elegans homolog snx6). Retromer was recruited to the surfaces of phagosomes containing cell corpses, and its loss of function caused defective cell corpse removal. The retromer probably acted through direct interaction with CED1 in the cell corpse recognition pathway. In the absence of retromer function, CED1 associated with lysosomes and failed to recycle from phagosomes and cytosol to the plasma membrane. Thus, Chen et al. (2010) concluded that retromer is an essential mediator of apoptotic cell clearance by regulating phagocytic receptor(s) during cell corpse engulfment.

Ranganathan et al. (2011) noted that previous work (Cao et al., 2006) had shown colocalization of LRP1 with integrin alpha-M (ITGAM; 120980)/beta-2 (ITGB2; 600065) at the trailing edge of migrating macrophages and that macrophage migration depended upon coordinated action of LRP1 and alpha-M/beta-2, as well as tissue plasminogen activator and its inhibitor, PAI1 (SERPINE1; 173360). Ranganathan et al. (2011) found that LRP1 specifically bound integrin alpha-M/beta-2, but not the homologous receptor integrin alpha-L (ITGAL; 153370)/beta-2. Activation of alpha-M/beta-2 by lipopolysaccharide (LPS) enhanced interaction between LRP1 and alpha-M/beta-2 in macrophages. Transfection experiments in HEK293 cells revealed that both the heavy and light chains of LRP1 contributed to alpha-M/beta-2 binding. Within the LRP1 heavy chain, binding was mediated primarily via ligand-binding motifs 2 and 4. Within alpha-M, the sequence EQLKKSKTL within the I domain was the major LRP1 recognition site. Exposure of alpha-M/beta-2-expressing HEK293 cells to soluble LRP1 inhibited cell attachment to fibrinogen (see 134820). Mouse macrophages lacking Lrp1 were deficient in alpha-M/beta-2 internalization upon LPS stimulation. Ranganathan et al. (2011) concluded that LRP1 has a role in macrophage migration and that it is critical for internalization of integrin alpha-M/beta-2.

Rauch et al. (2020) showed that LRP1 controls the endocytosis of tau (157140) and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Rauch et al. (2020) concluded that their results identified LRP1 as a key regulator of tau spread in the brain.


Molecular Genetics

Keratosis Pilaris Atrophicans

In 4 affected children from a consanguineous Pakistani family with keratosis pilaris atrophicans mapping to chromosome 12q (KPA; 604093), Klar et al. (2015) identified homozygosity for a missense mutation in the LRP1 gene (K1245R; 107770.0002). The mutation segregated fully with disease in the family and was not found in 200 Swedish or 200 Pakistani control chromosomes, in 900 in-house exomes, or in the dbSNP, EVS, ESP, or ExAC databases.

Developmental Dysplasia of the Hip 3

In 2 mother-daughter pairs from 2 Han Chinese families and in 7 unrelated Han Chinese children with developmental dysplasia of the hip (DDH3; 620690), Yan et al. (2022) identified heterozygosity for mutations in the LRP1 gene, including 7 missense variants and 3 splice site variants (see, e.g., 107770.0005-107770.0008). Functional analysis suggested that the variants cause LRP1 loss of function with a gene dosage effect, and analysis of a mouse model demonstrated premature fusion of the Y-shaped triradiate cartilage of the acetabulum, inhibiting bidirectional growth and resulting in the abnormally small acetabulum.

Association with Alzheimer Disease

The low density lipoprotein receptor-related protein gene was an attractive candidate for Alzheimer disease (AD) for several reasons. The multifunctional LRP had been shown to function as a receptor for the uptake of apolipoprotein E-containing lipoprotein particles by neurons. The apoE4 (107741) allele is strongly associated with an increased risk of late-onset familial Alzheimer disease and both late-onset and early-onset sporadic AD. The LRP receptor is prominently located in the soma regions and proximal processes of neurons. In a case-control study of 183 familial and sporadic AD patients and 118 controls, Lendon et al. (1997) found a moderate association (odds ratio = 1.57, p = 0.024) between AD and the 87-bp allele of a tetranucleotide repeat polymorphism located 5-prime to the LRP1 gene. Furthermore, Pericak-Vance et al. (1997) found in a genomic screen and follow-up analysis of 54 late-onset AD families, 4 regions potentially harboring AD genes; one of these regions, on chromosome 12, was located about 10 cM proximal of LRP1. Scott et al. (1998) examined 144 late-onset multiplex AD families, 436 sporadic AD cases, and 240 controls and found no evidence of linkage or association of LRP1 and AD. Their data indicated that genetic variation in the LRP1 gene is not a major risk factor in the etiology of Alzheimer disease.

Among 157 patients with late-onset AD (85 with a family history and 72 without a family history), Kang et al. (1997) found increased frequency of the C allele of a 766C-T polymorphism in exon 3 of the LRP1 gene compared to controls, although the C allele was common in controls. The authors suggested that the polymorphism, predicted to be silent, may be in linkage disequilibrium with a putative nearby AD susceptibility locus. Studies by Hollenbach et al. (1998) and Baum et al. (1998) also provided evidence of increased frequency of the 766C allele in patients with AD. McIlroy et al. (2001) found no association with the exon 3 polymorphism and development of AD.

Kang et al. (2000) noted that LRP and its ligands, APOE and alpha-2-macroglobulin, are all genetically associated with AD.

Bian et al. (2005) investigated the potential genetic contribution of 4 polymorphisms in LRP1 to AD in the Han Chinese population by studying 216 late-onset AD patients and 200 control subjects. The LRP1 CTCG haplotype (exon 3 T/C; intron 6 T/C, rs2306692; exon 22 T/C; intron 83 A/G, rs1800164) was overrepresented in the control group (p = 0.002). This difference was still statistically significant in the APOE4-negative subjects (p = 0.003), indicating that the CTCG haplotype of LRP1 may reduce the risk for late-onset AD.

Associations Pending Confirmation

For discussion of a possible association between variation in the LRP1 gene and abdominal aortic aneurysm, see AAA4 (614375).

For discussion of mutation in the LRP1 gene as a possible cause of intellectual disability, see 107770.0001.

For discussion of a possible association between a syndrome involving ascites, congenital heart defects, cardiopulmonary dysfunction, and dysmorphic features and variation in the LRP1 gene, see 107770.0003.


Animal Model

Boucher et al. (2003) developed tissue-specific knockout mice that lacked Lrp1 only in vascular smooth muscle cells. To increase susceptibility to spontaneous atherosclerotic lesion development, these animals were crossed to LDL receptor (Ldlr; 606945) knockout mice to generate Ldlr-/smooth muscle Lrp- mice. The presence or absence of Lrp1 expression in smooth muscle cells had no effect on plasma cholesterol or triglyceride levels in mice on normal chow or an atherogenic high-cholesterol diet. However, aortas from smooth muscle Lrp- mice were consistently distended and dilated. This difference increased over time and was accompanied by thickening of the aortic wall, pronounced atherosclerosis, and aneurysm formation. Boucher et al. (2003) showed that Lrp1 forms a complex with the PDGF receptor (see PDGFR1, 173410). Inactivation of Lrp1 in vascular smooth muscle cells of mice caused PDGFR overexpression and abnormal activation of PDGFR signaling, resulting in disruption of the elastic layer, smooth muscle cell proliferation, aneurysm formation, and marked susceptibility to cholesterol-induced atherosclerosis. The development of these abnormalities was reduced by treatment with Gleevec, an inhibitor of PDGF signaling. Thus, Boucher et al. (2003) concluded that LRP1 has a pivotal role in protecting vascular wall integrity and preventing atherosclerosis by controlling PDGFR activation.

May et al. (2004) found that mice with targeted disruption of the Lrp1 gene in differentiated postmitotic neurons demonstrated hyperactivity and constant tremor, and later developed dystonic posturing with increased thoracic kyphosis, waddling gait, and hindlimb weakness, suggesting motoneuronal disinhibition or motor excitation. The transgenic mice died prematurely at about 9 months of age. Brain morphology was normal with no major neuronal loss, suggesting a functional abnormality in neurotransmission. In vitro, LRP1 coimmunoprecipitated and colocalized with the postsynaptic protein PSD95 (602887) and the N-methyl-D-aspartate (NMDA) receptor subunits NR2A (138253) and NR2B (138252). Treatment of neurons with NMDA reduced the interaction of Lrp1 and Psd95. May et al. (2004) concluded that LRP1 plays a role in behavior and motor function by regulating postsynaptic signaling mechanisms through interaction with NMDA receptors.

Hofmann et al. (2007) generated mice with adipocyte-specific inactivation of LRP1 and observed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. In addition, the mutant mice were resistant to dietary fat-induced obesity and glucose intolerance. Hofmann et al. (2007) concluded that LRP1 is a critical regulator of adipocyte energy homeostasis.

Using the CRISPR/Cas9 genome editing system, Yan et al. (2022) established a knockin mouse line (KI) with an Lrp1 R1783W substitution, the same LRP1 variant that they had identified in a mother and daughter with developmental dysplasia of the hip (DDH3; see 107770.0005). They also generated heterozygous Lrp1 knockout (KO) mice (homozygous KO mice were not obtained). Western blot and protein mass spectrometry analyses showed significant reductions in expression levels of Lrp1 in the mutants compared to wildtype mice, with heterozygous KI mice having expression levels of Lrp1 between those of wildtype and homozygous KI mice, and KI homozygotes having levels similar to those of the KO heterozygotes. Micro-CT analysis of the hip joint showed a dramatic reduction of the acetabular volume in KI homozygotes and KI and KO heterozygotes compared to wildtype mice, with defective coverage of the femoral head. Acetabular volumes of the mutant mice were consistent with the Lrp1 expression levels, with KI heterozygotes having a smaller acetabulum than wildtype mice, but larger than KI homozygotes. Histologic analysis of hip joint sections revealed that the Y-shaped triradiate acetabular cartilage had closed completely before 6 weeks in KI and KO mice, whereas it closed after 8 weeks in wildtype mice. The authors suggested that the premature fusion associated with Lrp1 deficiency inhibits bidirectional growth of the triradiate cartilage, resulting in an abnormally small acetabulum. Proteome experiments showed a significant reduction in collagen expression in the hip joints of both heterozygous and homozygous KI mice compared to wildtype littermates, and autophagy proteins were significantly increased, with both presenting a dosage effect. In addition, Lrp1 deficiency caused a significant decrease of chondrogenic ability in vitro. During the chondrogenic induction of mouse bone marrow stem cells and ATDC5 (an inducible chondrogenic cell line), Lrp1 deficiency caused decreased autophagy levels with significant beta-catenin (CTNNB1; 116806) upregulation and suppression of chondrocyte marker genes. The expression of chondrocyte markers was rescued by PNU-74654 (a beta-catenin antagonist) in an shRNA-Lrp1-expressed ATDC5 cell. The authors concluded that LRP1 plays a critical role in the etiology and pathogenesis of DDH.


ALLELIC VARIANTS 8 Selected Examples):

.0001   VARIANT OF UNKNOWN SIGNIFICANCE

LRP1, HIS3258GLN
SNP: rs1565750061, ClinVar: RCV000033099, RCV001843464

This variant is classified as a variant of unknown significance because its contribution to intellectual disability has not been confirmed.

In a boy who developed seizures and developmental stagnation at age 22 months and ultimately had severe intellectual disability with an IQ of 34, stereotypic behavior, high pain threshold, and sleep disturbances with a normal brain MRI and no dysmorphic features, de Ligt et al. (2012) identified a de novo heterozygous 9774C-G transversion resulting in a his3258-to-gln (H3258Q) substitution.


.0002   KERATOSIS PILARIS ATROPHICANS (1 family)

LRP1, LYS1245ARG
SNP: rs483353013, gnomAD: rs483353013, ClinVar: RCV000119304, RCV000258847

In 4 affected children from a consanguineous Pakistani family with a mixed type of keratosis pilaris atrophicans (KPA; 604093), Klar et al. (2015) identified homozygosity for a c.3734A-G transition (c.3734A-G, NM_002332.2) in exon 23 of the LRP1 gene, resulting in a lys1245-to-arg (K1245R) substitution at a highly conserved residue within the sixth epidermal growth factor (EGF)-like domain. The mutation segregated fully with disease in the family and was not found in 200 Swedish or 200 Pakistani control chromosomes, in 900 in-house exomes, or in the dbSNP, EVS, ESP, or ExAC databases. Analysis of mRNA from patient fibroblast cultures showed a 5-fold reduction in LRP1 mRNA compared to age-matched controls; immunostaining and fluorescence confocal microscopy confirmed significantly reduced LRP1 levels in patient cells compared to controls. In addition, there was a marked reduction in cellular uptake of the known LRP1 ligand A2M (103950) in patient fibroblasts compared to controls, and intracellular A2M levels were reduced beyond what would be expected from the LRP1 levels (p = 0.0017) compared to controls, suggesting that binding properties of LRP1 to A2M were altered in the patients.


.0003   VARIANT OF UNKNOWN SIGNIFICANCE

LRP1, CYS3807SER
ClinVar: RCV003147750

This variant is classified as a variant of unknown significance because its contribution to a syndrome involving ascites, congenital heart defects, cardiopulmonary dysfunction, and dysmorphic features has not been confirmed.

In a sister and brother with ascites, congenital heart defects, cardiopulmonary dysfunction, and dysmorphic features, Mark et al. (2022) performed rapid genome sequencing and identified compound heterozygosity for 2 missense mutations in the LRP1 gene: a c.11420G-C transversion (SCV002569952), resulting in a cys3807-to-ser (C3807S) substitution, and a c.12407T-G transversion, resulting in a val4136-to-gly (V4136G; 107770.0004) substitution, both at highly conserved residues. Their unaffected parents were heterozygous for the variants, which were not found in the gnomAD database. Both sibs were born with severe respiratory distress requiring intubation and mechanical ventilation. Other overlapping features included prenatal detection of polyhydramnios, cerebral ventriculomegaly, and fetal ascites, and postnatal observation of hypotonia, large anterior fontanel, hypertelorism, prominent under-orbital creases, corneal clouding, low-set ears, large patent ductus arteriosus, coarctation of the aorta, massive ascites, cerebral ventriculomegaly, and paddle-shaped fingertips and toes. Additional features in the sister included cleft soft palate, upslanting palpebral fissures, hypoplastic aortic valve, patent foramen ovale, dysplastic pulmonary valve, and single palmar creases. She developed pulmonary hypertension and severe hypertrophic cardiomyopathy. She had stable hepatomegaly, with clinical resolution of ascites over time. Ophthalmologic assessment revealed glaucoma, and she had enlarged pupils and irises. Additional features in the brother included large size for gestational age, single umbilical artery, large ventricular septal defect, undescended and nonpalpable testes, and no spontaneous movement. He required paracentesis of ascites in the delivery room to allow for lung expansion, and had bilateral hydronephrosis with proximal hydroureter. The sister died at 5 months of age due to cardiac arrest; the brother, who was hypotonic, unresponsive, and oliguric after birth was extubated on day 2 of life and expired shortly thereafter. The authors stated that mouse-model phenotypes present in Lrp1 knockouts aligned with features observed in the affected sibs.


.0004   VARIANT OF UNKNOWN SIGNIFICANCE

LRP1, VAL4136GLY
ClinVar: RCV003147749

For discussion of the c.12407T-G transversion (SCV002569951) in the LRP1 gene, resulting in a val4136-to-gly (V4136G) substitution, that was found in compound heterozygous state in 2 sibs with ascites, congenital heart defects, cardiopulmonary dysfunction, and dysmorphic features by Mark et al. (2022), see 107770.0003.


.0005   DEVELOPMENTAL DYSPLASIA OF THE HIP 3

LRP1, ARG1783TRP
ClinVar: RCV003493368

In a 2-year-old Han Chinese girl (patient 2621) with bilateral developmental dysplasia of the hip (DDH3; 620690), Yan et al. (2022) identified heterozygosity for a c.5347C-T transition (c.5347C-T, NM_002332) in exon 32 of the LRP1 gene, resulting in an arg1783-to-trp (R1783W) substitution at a highly conserved residue. Her affected mother was also heterozygous for the mutation, which was present at low minor allele frequency (MAF 0.0001) in the East Asian population of the ExAC database and at very low MAF (2.785 x 10(-5)) in the gnomAD database; the variant was not found in the 1000 Genomes Project or ESP6500 databases. Using the CRISPR/Cas9 genome editing system, the authors generated a knockin mouse line (KI) with an Lrp1 R1783W substitution. Western blot and protein mass spectrometry analyses showed that heterozygous KI mice had expression levels of Lrp1 that were between those of wildtype and homozygous KI mice, and that the homozygous KI levels were similar to those of mice with heterozygous knockout of Lrp1. In addition, acetabular volumes of the mutant mice were consistent with the Lrp1 expression levels, with KI heterozygotes having a smaller acetabulum than wildtype mice, but larger than KI homozygotes. The authors suggested that the R1783 mutant causes loss of function with a gene dosage effect.


.0006   DEVELOPMENTAL DYSPLASIA OF THE HIP 3

LRP1, THR2129LYS
ClinVar: RCV003493369

In a 1.5-year-old Han Chinese girl (patient 2726) with unilateral developmental dysplasia of the hip (DDH3; 620690), Yan et al. (2022) identified heterozygosity for a c.6386C-A transversion (c.6386C-A, NM_002332) in exon 40 of the LRP1 gene, resulting in a thr2129-to-lys (T2129K) substitution at a highly conserved residue. Her affected mother was also heterozygous for the mutation, which was present at low minor allele frequency (MAF 0.0006) in the East Asian population of the ExAC database and at very low MAF (2.784 x 10(-5)) in the gnomAD database; the variant was not found in the 1000 Genomes Project or ESP6500 databases.


.0007   DEVELOPMENTAL DYSPLASIA OF THE HIP 3

LRP1, PRO224ALA
ClinVar: RCV003493370

In a 5-month-old Han Chinese infant (patient 3193) with unilateral developmental dysplasia of the hip (DDH3; 620690), Yan et al. (2022) identified heterozygosity for a c.670C-G transversion (c.670C-G, NM_002332) in exon 6 of the LRP1 gene, resulting in a pro224-to-ala (P224A) substitution. The variant was not found in the East Asian population of the ExAC database or in the gnomAD, 1000 Genomes Project, or ESP6500 databases; familial segregation was not reported.


.0008   DEVELOPMENTAL DYSPLASIA OF THE HIP 3

LRP1, IVS17AS, C-A, -4
ClinVar: RCV003493371

In an 8-month-old Han Chinese infant (patient 3196) with unilateral developmental dysplasia of the hip (DDH3; 620690), Yan et al. (2022) identified heterozygosity for a splice site mutation in intron 17 of the LRP1 gene (c.2798-4C-A, NM_002332). The variant was present at low minor allele frequency (MAF 0.0001) in the East Asian population of the ExAC database and at very low MAF (2.023 x 10(-5)) in the gnomAD database; the variant was not found in the 1000 Genomes Project or ESP6500 databases. Familial segregation was not reported.


See Also:

Beisiegel et al. (1989)

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Contributors:
Marla J. F. O'Neill - updated : 01/26/2024
Marla J. F. O'Neill - updated : 01/03/2023
Ada Hamosh - updated : 08/14/2020
Marla J. F. O'Neill - updated : 11/11/2016
Patricia A. Hartz - updated : 6/11/2013
Ada Hamosh - updated : 2/13/2013
Marla J. F. O'Neill - updated : 12/2/2011
Patricia A. Hartz - updated : 4/19/2011
Ada Hamosh - updated : 4/22/2010
Patricia A. Hartz - updated : 3/13/2008
Marla J. F. O'Neill - updated : 1/17/2008
John Logan Black, III - updated : 7/12/2006
Ada Hamosh - updated : 2/1/2006
Patricia A. Hartz - updated : 11/9/2005
Cassandra L. Kniffin - updated : 11/15/2004
Ada Hamosh - updated : 9/23/2003
Cassandra L. Kniffin - updated : 6/3/2003
Ada Hamosh - updated : 4/22/2003
Paul J. Converse - updated : 10/29/2001
Paul J. Converse - updated : 9/15/2000
Victor A. McKusick - updated : 5/5/1998

Creation Date:
Victor A. McKusick : 11/23/1988

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carol : 7/12/2006
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alopez : 2/2/2006
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mgross : 12/2/2005
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terry : 4/22/2003
ckniffin : 6/5/2002
cwells : 10/29/2001
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mgross : 9/15/2000
psherman : 10/14/1998
dholmes : 7/2/1998
carol : 5/14/1998
carol : 5/12/1998
terry : 5/5/1998
carol : 8/3/1994
warfield : 3/11/1994
carol : 6/17/1993
carol : 9/22/1992
carol : 6/1/1992
supermim : 3/16/1992