Alternative titles; symbols
HGNC Approved Gene Symbol: LTBP2
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38): 14:74,498,183-74,612,237 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.3 | ?Weill-Marchesani syndrome 3, recessive | 614819 | Autosomal recessive | 3 |
| Glaucoma 3, primary congenital, D | 613086 | 3 | ||
| Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma | 251750 | Autosomal recessive | 3 |
LTBP2 encodes an extracellular matrix (ECM) protein that is expressed in elastic tissues and associates with fibrillin-1 (FBN1; 134797)-containing microfibrils (summary by Haji-Seyed-Javadi et al., 2012).
Moren et al. (1994) identified a novel latent transforming growth factor-beta binding protein (see LTBP1; 150390), designated LTBP2.
Ali et al. (2009) characterized the LTBP2 gene. The 1,821-amino acid protein consists of 20 epidermal growth factor (EGF)-like domains, 4 transforming growth factor-beta binding protein (TB)-like modules each containing 8 cysteine residues, and an N-terminal signal peptide. Sixteen of the EGF domains have calcium-binding motifs, and it had been suggested that these adopt a rod-like molecular arrangement upon calcium binding in order to present a specific surface for protein-protein interactions. The cysteine-containing TB domains are unique features of the LTBP-fibrillin superfamily, providing a degree of conformational flexibility. LTBP2 has approximately 45% amino acid identity to LTBP1 and 25% identity to fibrillin-1 (FBN1; 134797) but unlike other LTBP family members does not bind to latent forms of TGFB (190180). The C-terminal region of LTBP2 competes with LTBP1 for specific binding to the N-terminal region of FBN1, but not FBN2 (612570), in microfibrils.
By RT-PCR analysis, Narooie-Nejad et al. (2009) showed high LTBP2 expression in human eyes, including the trabecular meshwork and ciliary processes that are thought to be relevant to the etiology of primary congenital glaucoma. Immunohistochemical analysis of human eye showed highest LTBP2 expression in the Descemet membrane and in the lens capsule, with expression also in the nonpigmented epithelium of the ciliary processes, trabecular meshwork, and transitional zone between the sclera and corneal stroma. Expression was minimal in corneal stroma, sclera, and iris.
See Oklu and Hesketh (2000) for a review of the LTBP gene family.
Ali et al. (2009) determined that the LTBP2 gene comprises 35 exons.
Moren et al. (1994) mapped the LTBP2 gene to chromosome 14q24 by analysis of somatic cell hybrids and by fluorescence in situ hybridization.
Primary Congenital Glaucoma 3D
In 4 consanguineous Pakistani families and in 8 Gypsy individuals with primary congenital glaucoma (GLC3D; 613086), Ali et al. (2009) identified homozygous nonsense mutations in the LTBP2 gene. The data suggested that R299X (602091.0001) is the major primary congenital glaucoma founder mutation in the Gypsy population.
In 2 consanguineous Iranian families with primary congenital glaucoma, Narooie-Nejad et al. (2009) independently identified respective homozygous 1-bp deletions (602091.0006-602091.0007).
In 12 Roma/Gypsy probands with congenital glaucoma, Azmanov et al. (2011) identified homozygosity for the R299X founder mutation. In an additional patient, they identified compound heterozygosity for R299X and a missense mutation in the CYP1B1 gene (R368H; 601771.0012). However, the authors stated that their preliminary observations suggested that CYP1B1/LTBP2 combinations in this and other patients were of no clinical significance and that digenic inheritance was unlikely.
Microspherophakia and/or Megalocornea, with Ectopia Lentis and with or without Secondary Glaucoma
In 3 affected brothers from a consanguineous Indian family with isolated microspherophakia and lens dislocation mapping to chromosome 14q24-q32.12 (MSPKA; 251750), Kumar et al. (2010) identified homozygosity for a frameshift mutation in the LTBP2 gene (602091.0005). Primary congenital glaucoma was excluded in the affected sibs, and none had any systemic involvement.
In 3 affected sibs from a consanguineous Moroccan family with megalocornea, microspherophakia, ectopia lentis, and secondary glaucoma mapping to chromosome 14q23.3-q24.3, Desir et al. (2010) analyzed the candidate gene LTBP2 and identified homozygosity for a 1-bp insertion (602091.0008). In a similarly affected girl of Macedonian Gypsy origin, they identified homozygosity for the R299X mutation in LTBP2, previously identified in patients with primary congenital glaucoma, including patients of European Gypsy origin.
In 8 affected individuals from 3 consanguineous families with megalocornea and secondary glaucoma due to spherophakia and/or ectopia lentis, Khan et al. (2011) identified homozygosity for a 1-bp deletion, a nonsense mutation, and a missense mutation (602091.0009-602091.0011, respectively).
Weill-Marchesani Syndrome 3
In affected members of a large consanguineous Iranian family with Weill-Marchesani syndrome (WMS3; 614819), Haji-Seyed-Javadi et al. (2012) identified homozygosity for a missense mutation (V1177M; 602091.0012) in the LTBP2 gene.
Shipley et al. (2000) targeted disruption of Ltbp2 in mice. All died between embryonic day 3.5 and 6.5. Ali et al. (2009) found expression of mouse Ltbp2 in connective tissue throughout the body and in particular spinal cord, cardiac, and skeletal muscles as well as renal and seminiferous tubules.
The symbol LTBP3 was formerly used for LTBP2 in the literature, but LTBP3 is the official symbol for a different LTBP gene; see 602090.
In affected members of a consanguineous Pakistani family with congenital glaucoma (GLC3D; 613086), Ali et al. (2009) identified homozygosity for a C-to-T transition at nucleotide 895 in exon 4 of the LTBP2 gene, resulting in an arg-to-ter substitution at codon 299 (R299X).
Ali et al. (2009) also identified this mutation in 8 of 15 CYP1B1 (601771)-negative Gypsy patients. The authors suggested that R299X is the major founder mutation in the Gypsy population, accounting for more than 50% of CYP1B1-negative and nearly 40% of all PCG cases in that population.
In 12 Roma/Gypsy probands with congenital glaucoma, Azmanov et al. (2011) identified homozygosity for the R299X founder mutation. In an additional patient, they identified compound heterozygosity for R299X and a missense mutation in the CYP1B1 gene (R368H; 601771.0012). However, the authors stated that their preliminary observations suggested that CYP1B1/LTBP2 combinations in this and other patients were of no clinical significance and that digenic inheritance was unlikely.
In a 3-year-old girl of Macedonian Gypsy origin with megalocornea, microspherophakia, and lens dislocation (MSPKA; 251750), Desir et al. (2010) identified homozygosity for the R299X mutation in the LTBP2 gene. Her unaffected parents were heterozygous for the mutation, which was not found in 100 Caucasian controls. When initially seen at 2 years of age, she had normal eye pressures, and still had not developed glaucoma at 3 years of age.
In affected members of a consanguineous Pakistani family with congenital glaucoma (GLC3D; 613086), Ali et al. (2009) identified homozygosity for a single-nucleotide deletion at position 412 in exon 1 of the LTBP2 gene (412delG) resulting in a frameshift and leading to a putative stop codon 140 amino acids downstream (Ala138ProfsTer278).
In affected members of a consanguineous Pakistani family with congenital glaucoma (GLC3D; 613086), Ali et al. (2009) identified homozygosity for a 14-bp deletion in exon 6 of the LTBP2 gene beginning at nucleotide 1243 (1243-1256del), resulting in frameshift and premature protein termination (Glu415ArgfsTer596).
In affected members of a consanguineous Pakistani family with congenital glaucoma (GLC3D; 613086), Ali et al. (2009) identified homozygosity for a C-to-T transition at nucleotide 331 in exon 1 of the LTBP2 gene, resulting in a gln-to-ter substitution at codon 111 (Q111X).
In 3 affected brothers from a consanguineous Indian family with microspherophakia and lens dislocation (MSPKA; 251750), Kumar et al. (2010) identified homozygosity for a 1-bp insertion (5446insC) in exon 36 of the LTBP2 gene, predicted to elongate the LTBP2 protein by replacing the last 6 amino acids with 27 novel amino acids.
In a consanguineous Iranian family with primary congenital glaucoma (GLC3D; 613086), Narooie-Nejad et al. (2009) identified a homozygous 1-bp deletion (1415delC) in exon 7 of the LTBP2 gene, resulting in a frameshift and premature termination. The deletion was not identified in 400 control individuals.
In a consanguineous Iranian family with primary congenital glaucoma (GLC3D; 613086), Narooie-Nejad et al. (2009) identified a homozygous 1-bp deletion (5376delC) in exon 36 of the LTBP2 gene, resulting in the addition of 28 amino acids to the C terminus of the protein. The deletion was not identified in 400 control individuals.
In a brother and 2 sisters from a consanguineous Moroccan family with microspherophakia, megalocornea, lens dislocation, and secondary glaucoma (MSPKA; 251750), Desir et al. (2010) identified homozygosity for a 1-bp duplication (1796dupC) in exon 9 of the LTBP2 gene, causing a frameshift predicted to result in a premature termination codon (Val600GlyfsTer4). Their unaffected parents were heterozygous for the mutation, which was not found in 100 Moroccan controls. Analysis of mRNA from patient and control fibroblasts showed results consistent with nonsense-mediated mRNA decay. The oldest sib, a 14-year-old boy, displayed some marfanoid features (see Marfan syndrome, 154700) including arm span greater than height, decreased upper-to-lower body ratio, and high-arched palate.
In 2 male cousins, 2 years and 14 years old, from a consanguineous Saudi Arabian family with megalocornea, lens dislocation, and secondary glaucoma (MSPKA; 251750), Khan et al. (2011) identified homozygosity for a 1-bp deletion (1012delT) in exon 4 of the LTBP2 gene, causing a frameshift predicted to result in a premature termination codon (Ser338ProfsTer2). Their unaffected parents were all heterozygous for the mutation. The older boy was tall and thin with a relatively high-arched palate, but there were no other features to suggest Marfan syndrome (154700).
In 2 brothers from a consanguineous Saudi Arabian family with microspherophakia, megalocornea, lens dislocation, and secondary glaucoma (MSPKA; 251750), Khan et al. (2011) identified homozygosity for a 4855C-T transition in exon 33 of the LTBP2 gene, resulting in a gln1619-to-ter (Q1619X) substitution. Their unaffected parents were heterozygous for the mutation.
In 2 brothers from a consanguineous Saudi Arabian family with megalocornea, lens dislocation, and secondary glaucoma (MSPKA; 251750), 1 of whom also had microspherophakia, Khan et al. (2011) identified homozygosity for a 4313G-A transition in exon 29 of the LTBP2 gene, resulting in a cys1438-to-tyr (C1438Y) substitution at a conserved residue. Their affected father and an affected paternal aunt were also homozygous for the mutation, which was found in heterozygosity in the boys' unaffected mother but was not present in 100 ethnically matched controls.
In an affected brother and sister and their affected cousin from a large consanguineous Iranian family with Weill-Marchesani syndrome (WMS3; 614819), Haji-Seyed-Javadi et al. (2012) identified homozygosity for a 3529G-A transition in exon 24 of the LTBP2 gene, resulting in a val1177-to-met (V1177M) substitution at a highly conserved residue within the consensus calcium-binding sequence of the ninth calcium-binding epidermal growth factor (131530)-like motif. The mutation was also present in homozygosity in 3 more affected relatives who displayed some features of Weill-Marchesani syndrome but had no ocular abnormalities. Unaffected family members were either heterozygous or homozygous for wildtype LTBP2, and the mutation was not found in 400 ethnically matched controls. Histologic examination of the extracellular matrix (ECM) of skin fibroblasts from the proband revealed elastic fibers that appeared clumped and fragmented compared to a control, and electron micrography showed obvious disruption of the ECM in the patient's skin, with notable reduction in abundance of collagen fibers and increased space between adjacent fibers of the patient. Haji-Seyed-Javadi et al. (2012) concluded that the V1177M mutation disrupts microfibrils and causes changes in the substructure of the ECM.
Ali, M., McKibbin, M., Booth, A., Parry, D. A., Jain, P., Riazuddin, S. A., Hejtmancik, J. F., Khan, S. N., Firasat, S., Shires, M., Gilmour, D. F., Towns, K., and 12 others. Null mutations in LTBP2 cause primary congenital glaucoma. Am. J. Hum. Genet. 84: 664-671, 2009. [PubMed: 19361779] [Full Text: https://doi.org/10.1016/j.ajhg.2009.03.017]
Azmanov, D. N., Dimitrova, S., Florez, L., Cherninkova, S., Draganov, D., Morar, B., Saat, R., Juan, M., Arostegui, J. I., Ganguly, S., Soodyall, H., Chakrabarti, S., and 10 others. LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population. Europ. J. Hum. Genet. 19: 326-333, 2011. [PubMed: 21081970] [Full Text: https://doi.org/10.1038/ejhg.2010.181]
Desir, J., Sznajer, Y., Depasse, F., Roulez, F., Schrooyen, M., Meire, F., Abramowicz, M. LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma. Europ. J. Hum. Genet. 18: 761-767, 2010. [PubMed: 20179738] [Full Text: https://doi.org/10.1038/ejhg.2010.11]
Haji-Seyed-Javadi, R., Jelodari-Mamaghani, S., Paylakhi, S. H., Yazdani, S., Nilforushan, N., Fan, J.-B., Klotzle, B., Mahmoudi, M. J., Ebrahimian, M. J., Chelich, N., Taghiabadi, E., Kamyab, K., Boileau, C., Paisan-Ruiz, C., Ronaghi, M., Elahi, E. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum. Mutat. 33: 1182-1187, 2012. [PubMed: 22539340] [Full Text: https://doi.org/10.1002/humu.22105]
Khan, A. O., Aldahmesh, M. A., Alkuraya, F. S. Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma--a distinct phenotype caused by recessive LTBP2 mutations. Molec. Vis. 17: 2570-2579, 2011. [PubMed: 22025892]
Kumar, A., Duvvari, M. R., Prabhakaran, V. C., Shetty, J. S., Murthy, G. J., Blanton, S. H. A homozygous mutation in LTBP2 causes isolated microspherophakia. Hum. Genet. 128: 365-371, 2010. [PubMed: 20617341] [Full Text: https://doi.org/10.1007/s00439-010-0858-8]
Moren, A., Olofsson, A., Stenman, G., Sahlin, P., Kanzaki, T., Claesson-Welsh, L., ten Dijke, P., Miyazono, K., Heldin, C.-H. Identification and characterization of LTBP-2, a novel latent transforming growth factor-beta-binding protein. J. Biol. Chem. 269: 32469-32478, 1994. [PubMed: 7798248]
Narooie-Nejad, M., Paylakhi, S. H., Shojaee, S., Fazlali, Z., Kanavi, M. R., Nilforushan, N., Yazdani, S., Babrzadeh, F., Suri, F., Ronaghi, M., Elahi, E., Paisan-Ruiz, C. Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Hum. Molec. Genet. 18: 3969-3977, 2009. [PubMed: 19656777] [Full Text: https://doi.org/10.1093/hmg/ddp338]
Oklu, R., Hesketh, R. The latent transforming growth factor beta binding protein (LTBP) family. Biochem. J. 352: 601-610, 2000. [PubMed: 11104663]
Shipley, J. M., Mecham, R. P., Maus, E., Bonadio, J., Rosenbloom, J., McCarthy, R. T., Baumann, M. L., Frankfater, C., Segade, F., Shapiro, S. D. Developmental expression of latent transforming growth factor beta binding protein 2 and its requirement early in mouse development. Molec. Cell. Biol. 20: 4879-4887, 2000. [PubMed: 10848613] [Full Text: https://doi.org/10.1128/MCB.20.13.4879-4887.2000]