* 610937

RPGRIP1-LIKE; RPGRIP1L


Alternative titles; symbols

NEPHROCYSTIN 8; NPHP8
KIAA1005


HGNC Approved Gene Symbol: RPGRIP1L

Cytogenetic location: 16q12.2     Genomic coordinates (GRCh38): 16:53,598,153-53,703,859 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
16q12.2 ?COACH syndrome 3 619113 AR 3
Joubert syndrome 7 611560 AR 3
Meckel syndrome 5 611561 AR 3

TEXT

Cloning and Expression

By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1999) cloned RPGRIP1L, which they called KIAA1005. The deduced protein contains 1,055 amino acids. RT-PCR ELISA detected moderate expression in adult brain, weak expression in kidney, ovary, and spinal cord, and no expression in any other adult or fetal tissue examined. Within specific brain regions, moderate expression was detected in caudate nucleus and amygdala, and weak expression was detected in corpus callosum, subthalamic nucleus, and cerebellum.

Delous et al. (2007) determined that the RPGRIP1L protein comprises 1,315 residues and shares 31% identity with RPGRIP1 (605446), a protein present at the photoreceptor connecting cilium and mutated in Leber congenital amaurosis type VI (see LCA6; 605446). RPGRIP1L contains an N-terminal region with 5 coiled-coil domains, a C-terminal region homologous to the RPGR-interacting domain of RPGRIP1, and a central region with 2 protein kinase C conserved region 2 (C2) motifs. By RT-PCR and in situ hybridization analysis, Delous et al. (2007) found ubiquitous RPGRIP1L expression in human embryonic and fetal tissues, including brain, forelimbs, and kidney, confirming its importance in early development.

By RT-PCR analysis, Arts et al. (2007) detected strong expression of RPGRIP1L in adult human testis and kidney and fetal eye, brain, and kidney.


Gene Structure

Delous et al. (2007) determined that the RPGRIP1L gene contains 27 exons and spans about 103.2 kb. Exon 27 is noncoding.


Mapping

By radiation hybrid analysis, Nagase et al. (1999) mapped the KIAA1005 gene to chromosome 16. By positional cloning, Delous et al. (2007) mapped the RPGRIP1L gene to chromosome 16q12.2.


Gene Function

Delous et al. (2007) demonstrated that RPGRIP1L localized to primary cilia and centrosomes in ciliated Madin-Darby canine kidney (MDCK) II cells. RPGRIP1L colocalized at the basal body-centrosome complex with nephrocystin-4 (NPHP4; 607215), nephrocystin-6 (NPHP6; 610142), and the centrosome marker gamma-tubulin (TUBG1; 191135). Some cells showed punctate RPGRIP1L localization along the ciliary axoneme or in the cytoplasm during cell division.

Arts et al. (2007) found that the C2 domain of RPGRIP1L interacts with NPHP4 by GST pull-down and coimmunoprecipitation. Cellular immunohistochemical studies of different animal tissues, including retina, brain, and kidney, showed that RPGRIP1L localized to basal bodies and ciliary axonemes at the base of primary cilia, where it interacted with NPHP4.

Williams et al. (2011) showed that the conserved proteins Mks1 (609883), Mksr1 (B9D1), Mksr2 (B9D2; 611951), Tmem67 (609884), Rpgrip1l, Cc2d2a (612013), Nphp1 (607100), and Nphp4 functioned at an early stage of ciliogenesis in C. elegans. These 8 proteins localized to the ciliary transition zone and established attachments between the basal body and transition zone membrane. They also provided a docking site that restricted vesicle fusion to vesicles containing ciliary proteins.


Molecular Genetics

Joubert Syndrome 7

In patients with Joubert syndrome (JBTS7; 611560), Delous et al. (2007) identified homozygous or compound heterozygous mutations in the RPGRIP1L gene (610937.0001-610937.0004). All patients had renal disease in addition to the classic neurologic abnormalities of Joubert syndrome.

In patients with JBTS7, Arts et al. (2007) identified homozygous or compound heterozygous mutations in the RPGRIP1L gene (see, e.g., 610937.0008-610937.0009). The phenotype was variable with respect to renal disease. None of the patients had retinal disease.

Wolf et al. (2007) identified 4 different RPGRIP1L mutations in 5 of 56 families with Joubert syndrome who were negative for mutations in other Joubert-related genes. Two families had the same mutation (T615P; 610937.0002). All patients with RPGRIP1L mutations had nephronophthisis (NPHP) with impaired renal function and mental retardation. Additional variable features included oculomotor apraxia, liver fibrosis, cerebellar vermis hypoplasia, impaired vision, and ocular coloboma. Only 1 patient had retinitis pigmentosa.

Meckel Syndrome 5

In 3 patients with Meckel syndrome type 5 (MKS5; 611561), Delous et al. (2007) identified homozygous or compound heterozygous truncating mutations in the RPGRIP1L gene (610937.0005-610937.0007). The results indicated that complete loss of RPGRIP1L results in the more severe phenotype of Meckel syndrome, whereas partial loss results in the less severe Joubert syndrome. However, the authors noted that both phenotypes result from the same underlying defect and thus represent a phenotypic spectrum.

COACH Syndrome 3

Doherty et al. (2010) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene (610937.0011 and 610937.0012) in a patient with a diagnosis of COACH syndrome (COACH3; 619113), defined as Joubert syndrome with congenital hepatic fibrosis. Other features in this patient included mental retardation, the molar tooth sign on brain MRI, and nephronophthisis. The findings indicated that COACH syndrome can be considered a subtype of Joubert syndrome with liver involvement. The proposed ciliary function for RPGRIP1L supported a unifying underlying pathophysiology for liver disease in these disorders.

Retinitis Pigmentosa in Ciliopathies, Modifier of

Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene (A229T; 610937.0013) may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations.


Animal Model

Delous et al. (2007) found that Rpgrip1l-null mouse fetuses had head abnormalities ranging from pronounced rounded shape of the skull to exencephaly. The eyes were either not detectable or small and deep-set. Cleft upper lips and hypoplastic lower jaws were frequent. There were multiple brain anomalies, including dilated ventricles, cerebellar hypoplasia, and absence of the corpus callosum. Some of the fetuses at later gestation showed microcystic dilatations of proximal kidney tubules and bile duct proliferation in the liver.

Laclef et al. (2015) had previously found that forebrain neuroepithelial cells of Rpgrip1l -/- mouse embryos had abnormal cilia devoid of axoneme. Rpgrip1l -/- telencephalon also showed severe ventrilization, which led to agenesis of olfactory bulbs and formation of ectopic olfactory bulb-like structures. Laclef et al. (2015) found that Rpgrip1l -/- guidepost and progenitor cells, which are involved in corpus callosum formation, also failed to form proper cilia. The coirticoseptal boundary in medial telencephalon of embryonic day-15.5 (E15.5) Rpgrip1l -/- embryos was severely perturbed, with cells of ventral identity present in the dorsal compartment and vice versa. Rpgrip1l -/- mutants also showed misexpression of several guidance molecules, including netrin-1 (NTN1; 601614) and Slit2 (603746). Patterning of commissural plate was already affected in E12.5 mutants. Reintroduction of the short repressor isoform of Gli3 (165240), Gli3r, restored normal telencephalic midline patterning and corpus collosum formation in the absence of primary cilia in Rpgrip1l -/- embryos.


ALLELIC VARIANTS ( 13 Selected Examples):

.0001 JOUBERT SYNDROME 7

RPGRIP1L, LYS233TER
  
RCV000001123...

In a French patient with Joubert syndrome (JBTS7; 611560), Delous et al. (2007) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene: a 697A-T transversion in exon 6 resulting in a lys233-to-ter (K233X) substitution, and a T615P (610937.0002) mutation. The child had mental retardation, cerebellar ataxia, nephronophthisis, oculomotor apraxia, ptosis, and genu valgum. End-stage renal disease occurred at age 6 years.


.0002 JOUBERT SYNDROME 7

RPGRIP1L, THR615PRO
  
RCV000001124...

In a French patient with Joubert syndrome (JBTS7; 611560), Delous et al. (2007) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene: a 1843A-C transversion in exon 15 of the RPGRIP1L gene resulting in a thr615-to-pro (T615P) substitution and a K233X (610937.0001) mutation. A second unrelated French patient with a similar phenotype was compound heterozygous for T615P and Q253X (610937.0003). Arts et al. (2007) found the T615P mutation in compound heterozygosity with a nonsense mutation (Q684X; 610937.0009) in a patient with Joubert syndrome.

Brancati et al. (2008) reported a brother and sister with Joubert syndrome who were homozygous for the T615P mutation. Both presented with developmental delay, growth and mental retardation, nephronophthisis, and severe scoliosis. Visual acuity, fundus examination, and liver function were normal. There was clinical variability between the 2 sibs regarding some features, with the sister being more severely affected. She died at age 17.5 years from renal failure, while he was still alive at age 22 years after kidney transplant. Both had the molar tooth sign on MRI.


.0003 JOUBERT SYNDROME 7

RPGRIP1L, GLN253TER
  
RCV000001125...

In a French patient with Joubert syndrome (JBTS7; 611560), Delous et al. (2007) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene: a 757C-T transition in exon 6 resulting in a gln253-to-ter (Q253X) substitution and a T615P (610937.0002) mutation. The patient had mental retardation, cerebellar ataxia, nephronophthisis, oculomotor apraxia, the molar tooth sign, ptosis, and scoliosis.


.0004 JOUBERT SYNDROME 7

RPGRIP1L, ALA695PRO
  
RCV000001126

In 2 French sibs with Joubert syndrome (JBTS7; 611560), Delous et al. (2007) identified a homozygous 2083G-C transversion in exon 15 of the RPGRIP1L gene, resulting in an ala695-to-pro (A695P) substitution. Both sibs had scoliosis, oculomotor apraxia, nystagmus, the molar tooth sign, and nephronophthisis with end-stage renal disease by age 9 years. Only 1 had mild mental retardation.


.0005 MECKEL SYNDROME, TYPE 5

RPGRIP1L, ARG132TER
  
RCV000001127...

In 2 presumably related Moroccan fetuses diagnosed with Meckel syndrome (MKS5; 611561) at 15 to 16 weeks' gestation by ultrasound, Delous et al. (2007) identified a homozygous 394A-T transversion in exon 4 of the RPGRIP1L gene, resulting in an arg132-to-ter (R132X) substitution. Post-termination examination showed anencephaly, occipital encephalocele, postaxial polydactyly, cleft lip and palate, microphthalmia, cystic kidney disease, and hepatic bile duct proliferation. One fetus showed bowing of the long bones. The severe phenotype corresponded to the complete loss of RPGRIP1L function.


.0006 MECKEL SYNDROME, TYPE 5

RPGRIP1L, GLN345TER
  
RCV000001128...

In a French fetus diagnosed with Meckel syndrome (MKS5; 611561) at 16 weeks' gestation by ultrasound, Delous et al. (2007) identified compound heterozygosity for 2 truncation mutations in the RPGRIP1L gene: a 1033C-T transition in exon 9 resulting in a gln345-to-ter (Q345X) substitution, and a 2614C-T transition in exon 17 resulting in a gln872-to-ter (Q872X; 610937.0007) substitution. Post-termination examination showed anencephaly, occipital encephalocele, postaxial polydactyly, cleft lip and palate, microphthalmia, cystic kidney disease, hepatic bile duct proliferation, and bowing of the long bones. The severe phenotype corresponded to the complete loss of RPGRIP1L function.


.0007 MECKEL SYNDROME, TYPE 5

RPGRIP1L, GLN872TER
  
RCV000033207...

For discussion of the gln872-to-ter (Q872X) mutation in the RPGRIP1L gene that was found in compound heterozygous state in a fetus diagnosed with Meckel syndrome (MKS5; 611561) by Delous et al. (2007), see 610937.0006.


.0008 JOUBERT SYNDROME 7

RPGRIP1L, 1-BP DEL, 1721A
  
RCV000201652

In a Turkish girl with Joubert syndrome (JBTS7; 611560), born of consanguineous parents, Arts et al. (2007) identified a homozygous 1-bp deletion (1721delA) in the RPGRIP1L gene, resulting in a frameshift and premature protein truncation before the C2 domain. The 10-year-old girl had molar tooth sign, hypotonia, ataxia, mental retardation, abnormal eye movements, and renal disease. Retinal disease was not present.


.0009 JOUBERT SYNDROME 7

RPGRIP1L, GLN684TER
  
RCV000001131...

In a patient with Joubert syndrome (JBTS7; 611560), Arts et al. (2007) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene: a 2050C-T transition, resulting in a gln684-to-ter (Q684X) substitution, and a T615P (610937.0002) mutation. The Q684X mutation was predicted to truncate the protein before the C2 domain. In vitro functional expression studies showed that both mutant proteins disrupted NPHP4 binding. At age 5, the child had the molar tooth sign, hypotonia, ataxia, mental retardation, abnormal eye movements, postaxial polydactyly, and encephalocele. Renal and retinal disease were not present.


.0010 JOUBERT SYNDROME 7

RPGRIP1L, 1-BP DEL, 2268A
  
RCV000001132

In a Moroccan girl with Joubert syndrome (JBTS7;611560), born of consanguineous parents, Brancati et al. (2008) identified a homozygous 1-bp deletion (2268delA) in exon 16 of the RPGRIP1L gene, resulting in a frameshift and premature protein truncation. She had episodes of hyperpnea and apnea and delayed milestones. At age 1 year, she developed renal dysfunction associated with small kidneys with increased echogenicity, loss of corticomedullary differentiation, and multiple cysts compatible with nephronophthisis. At age 4 years, she had chronic renal failure, marked growth retardation, and severe psychomotor delay with lack of head control and inability to speak any meaningful words. The molar tooth sign was present on MRI.


.0011 COACH SYNDROME 3 (1 patient)

RPGRIP1L, ARG805TER
  
RCV000001134...

In a 17-year-old male with COACH syndrome-3 (COACH3; 619113), defined as Joubert syndrome with liver disease, Doherty et al. (2010) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene: a 2413C-T transition, resulting in an arg805-to-ter (R805X) substitution, and a 1975T-C transition, resulting in a ser659-to-pro (S659P; 610937.0012) substitution. The patient had abnormal breathing pattern, mental retardation, molar tooth sign on brain MRI, congenital hepatic fibrosis with bile duct abnormalities, and nephronophthisis requiring renal transplant.


.0012 COACH SYNDROME 3 (1 patient)

RPGRIP1L, SER659PRO
  
RCV000001135...

For discussion of the ser659-to-pro (S659P) mutation in the RPGRIP1L gene that was found in compound heterozygous state in a patient with COACH syndrome-3 (COACH3; 619113) by Doherty et al. (2010), see 610937.0011.


.0013 RETINITIS PIGMENTOSA IN CILIOPATHIES, MODIFIER OF

RPGRIP1L, ALA229THR (rs61747071)
  
RCV000001133...

Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene, a 685G-A transition, resulting in an ala229-to-thr (A229T) substitution (rs61747071), may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations. The 229T allele was significantly enriched among a group of 487 patients with ciliopathy and retinal pigmentosa, including LCA (204000), Senior-Loken syndrome (266900), Joubert syndrome (213300), and BBS (209900), compared to 115 patients with ciliopathy without retinal pigmentosa, including NPHP (256100) and MKS (249000) (p = 1.66 x 10(-5)). In vitro functional expression studies showed that the 229T allele had decreased ability to bind to RPGR compared to the 229A allele.


REFERENCES

  1. Arts, H. H., Doherty, D., van Beersum, S. E. C., Parisi, M. A., Letteboer, S. J. F., Gorden, N. T., Peters, T. A., Marker, T., Voesenek, K., Kartono, A., Ozyurek, H., Farin, F. M., Kroes, H. Y., Wolfrum, U., Brunner, H. G., Cremers, F. P. M., Glass, I. A., Knoers, N. V. A. M., Roepman, R. Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nature Genet. 39: 882-888, 2007. [PubMed: 17558407, related citations] [Full Text]

  2. Brancati, F., Travaglini, L., Zablocka, D., Boltshauser, E., Accorsi, P., Montagna, G., Silhavy, J. L., Barrano, G., Bertini, E., Emma, F., Rigoli, L., the International JSRD Study Group, Dallapiccola, B., Gleeson, J. G., Valente, E. M. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin. Genet. 74: 164-170, 2008. [PubMed: 18565097, related citations] [Full Text]

  3. Delous, M., Baala, L., Salomon, R., Laclef, C., Vierkotten, J., Tory, K., Golzio, C., Lacoste, T., Besse, L., Ozilou, C., Moutkine, I., Hellman, N. E., and 25 others. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nature Genet. 39: 875-881, 2007. [PubMed: 17558409, related citations] [Full Text]

  4. Doherty, D., Parisi, M. A., Finn, L. S., Gunay-Aygun, M., Al-Mateen, M., Bates, D., Clericuzio, C., Demir, H., Dorschner, M., van Essen, A. J., Gahl, W. A., Gentile, M., and 11 others. Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J. Med. Genet. 47: 8-21, 2010. [PubMed: 19574260, images, related citations] [Full Text]

  5. Khanna, H., Davis, E. E., Murga-Zamalloa, C. A., Estrada-Cuzcano, A., Lopez, I., den Hollander, A. I., Zonneveld, M. N., Othman, M. I., Waseem, N., Chakarova, C. F., Maubaret, C., Diaz-Font, A., and 22 others. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nature Genet. 41: 739-745, 2009. [PubMed: 19430481, images, related citations] [Full Text]

  6. Laclef, C., Anselme, I., Besse, L., Catala, M., Palmyre, A., Baas, D., Paschaki, M., Pedraza, M., Metin, C., Durand, B., Schneider-Maunoury, S. The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor. Hum. Molec. Genet. 24: 4997-5014, 2015. [PubMed: 26071364, related citations] [Full Text]

  7. Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 63-70, 1999. [PubMed: 10231032, related citations] [Full Text]

  8. Williams, C. L., Li, C., Kida, K., Inglis, P. N., Mohan, S., Semenec, L., Bialas, N. J., Stupay, R. M., Chen, N., Blacque, O. E., Yoder, B. K., Leroux, M. R. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J. Cell. Biol. 192: 1023-1041, 2011. [PubMed: 21422230, images, related citations] [Full Text]

  9. Wolf, M. T. F., Saunier, S., O'Toole, J. F., Wanner, N., Groshong, T., Attanasio, M., Salomon, R., Stallmach, T., Sayer, J. A., Waldherr, R., Griebel, M., Oh, J., Neuhaus, T. J., Josefiak, U., Antignac, C., Otto, E. A., Hildebrandt, F. Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis. Kidney Int. 72: 1520-1526, 2007. [PubMed: 17960139, related citations] [Full Text]


Patricia A. Hartz - updated : 02/26/2016
Patricia A. Hartz - updated : 4/29/2011
Cassandra L. Kniffin - updated : 6/16/2010
Cassandra L. Kniffin - updated : 6/15/2009
Cassandra L. Kniffin - updated : 4/21/2009
Cassandra L. Kniffin - updated : 8/18/2008
Cassandra L. Kniffin - updated : 10/29/2007
Creation Date:
Patricia A. Hartz : 4/17/2007
carol : 12/01/2020
mgross : 02/26/2016
alopez : 4/22/2015
mcolton : 4/16/2015
carol : 1/18/2012
carol : 11/22/2011
mgross : 5/19/2011
mgross : 5/19/2011
terry : 4/29/2011
mgross : 4/28/2011
wwang : 6/24/2010
ckniffin : 6/16/2010
wwang : 6/18/2009
ckniffin : 6/15/2009
wwang : 4/30/2009
ckniffin : 4/21/2009
wwang : 8/25/2008
ckniffin : 8/18/2008
wwang : 11/16/2007
ckniffin : 10/29/2007
carol : 7/6/2007
mgross : 4/17/2007

* 610937

RPGRIP1-LIKE; RPGRIP1L


Alternative titles; symbols

NEPHROCYSTIN 8; NPHP8
KIAA1005


HGNC Approved Gene Symbol: RPGRIP1L

Cytogenetic location: 16q12.2     Genomic coordinates (GRCh38): 16:53,598,153-53,703,859 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
16q12.2 ?COACH syndrome 3 619113 Autosomal recessive 3
Joubert syndrome 7 611560 Autosomal recessive 3
Meckel syndrome 5 611561 Autosomal recessive 3

TEXT

Cloning and Expression

By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1999) cloned RPGRIP1L, which they called KIAA1005. The deduced protein contains 1,055 amino acids. RT-PCR ELISA detected moderate expression in adult brain, weak expression in kidney, ovary, and spinal cord, and no expression in any other adult or fetal tissue examined. Within specific brain regions, moderate expression was detected in caudate nucleus and amygdala, and weak expression was detected in corpus callosum, subthalamic nucleus, and cerebellum.

Delous et al. (2007) determined that the RPGRIP1L protein comprises 1,315 residues and shares 31% identity with RPGRIP1 (605446), a protein present at the photoreceptor connecting cilium and mutated in Leber congenital amaurosis type VI (see LCA6; 605446). RPGRIP1L contains an N-terminal region with 5 coiled-coil domains, a C-terminal region homologous to the RPGR-interacting domain of RPGRIP1, and a central region with 2 protein kinase C conserved region 2 (C2) motifs. By RT-PCR and in situ hybridization analysis, Delous et al. (2007) found ubiquitous RPGRIP1L expression in human embryonic and fetal tissues, including brain, forelimbs, and kidney, confirming its importance in early development.

By RT-PCR analysis, Arts et al. (2007) detected strong expression of RPGRIP1L in adult human testis and kidney and fetal eye, brain, and kidney.


Gene Structure

Delous et al. (2007) determined that the RPGRIP1L gene contains 27 exons and spans about 103.2 kb. Exon 27 is noncoding.


Mapping

By radiation hybrid analysis, Nagase et al. (1999) mapped the KIAA1005 gene to chromosome 16. By positional cloning, Delous et al. (2007) mapped the RPGRIP1L gene to chromosome 16q12.2.


Gene Function

Delous et al. (2007) demonstrated that RPGRIP1L localized to primary cilia and centrosomes in ciliated Madin-Darby canine kidney (MDCK) II cells. RPGRIP1L colocalized at the basal body-centrosome complex with nephrocystin-4 (NPHP4; 607215), nephrocystin-6 (NPHP6; 610142), and the centrosome marker gamma-tubulin (TUBG1; 191135). Some cells showed punctate RPGRIP1L localization along the ciliary axoneme or in the cytoplasm during cell division.

Arts et al. (2007) found that the C2 domain of RPGRIP1L interacts with NPHP4 by GST pull-down and coimmunoprecipitation. Cellular immunohistochemical studies of different animal tissues, including retina, brain, and kidney, showed that RPGRIP1L localized to basal bodies and ciliary axonemes at the base of primary cilia, where it interacted with NPHP4.

Williams et al. (2011) showed that the conserved proteins Mks1 (609883), Mksr1 (B9D1), Mksr2 (B9D2; 611951), Tmem67 (609884), Rpgrip1l, Cc2d2a (612013), Nphp1 (607100), and Nphp4 functioned at an early stage of ciliogenesis in C. elegans. These 8 proteins localized to the ciliary transition zone and established attachments between the basal body and transition zone membrane. They also provided a docking site that restricted vesicle fusion to vesicles containing ciliary proteins.


Molecular Genetics

Joubert Syndrome 7

In patients with Joubert syndrome (JBTS7; 611560), Delous et al. (2007) identified homozygous or compound heterozygous mutations in the RPGRIP1L gene (610937.0001-610937.0004). All patients had renal disease in addition to the classic neurologic abnormalities of Joubert syndrome.

In patients with JBTS7, Arts et al. (2007) identified homozygous or compound heterozygous mutations in the RPGRIP1L gene (see, e.g., 610937.0008-610937.0009). The phenotype was variable with respect to renal disease. None of the patients had retinal disease.

Wolf et al. (2007) identified 4 different RPGRIP1L mutations in 5 of 56 families with Joubert syndrome who were negative for mutations in other Joubert-related genes. Two families had the same mutation (T615P; 610937.0002). All patients with RPGRIP1L mutations had nephronophthisis (NPHP) with impaired renal function and mental retardation. Additional variable features included oculomotor apraxia, liver fibrosis, cerebellar vermis hypoplasia, impaired vision, and ocular coloboma. Only 1 patient had retinitis pigmentosa.

Meckel Syndrome 5

In 3 patients with Meckel syndrome type 5 (MKS5; 611561), Delous et al. (2007) identified homozygous or compound heterozygous truncating mutations in the RPGRIP1L gene (610937.0005-610937.0007). The results indicated that complete loss of RPGRIP1L results in the more severe phenotype of Meckel syndrome, whereas partial loss results in the less severe Joubert syndrome. However, the authors noted that both phenotypes result from the same underlying defect and thus represent a phenotypic spectrum.

COACH Syndrome 3

Doherty et al. (2010) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene (610937.0011 and 610937.0012) in a patient with a diagnosis of COACH syndrome (COACH3; 619113), defined as Joubert syndrome with congenital hepatic fibrosis. Other features in this patient included mental retardation, the molar tooth sign on brain MRI, and nephronophthisis. The findings indicated that COACH syndrome can be considered a subtype of Joubert syndrome with liver involvement. The proposed ciliary function for RPGRIP1L supported a unifying underlying pathophysiology for liver disease in these disorders.

Retinitis Pigmentosa in Ciliopathies, Modifier of

Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene (A229T; 610937.0013) may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations.


Animal Model

Delous et al. (2007) found that Rpgrip1l-null mouse fetuses had head abnormalities ranging from pronounced rounded shape of the skull to exencephaly. The eyes were either not detectable or small and deep-set. Cleft upper lips and hypoplastic lower jaws were frequent. There were multiple brain anomalies, including dilated ventricles, cerebellar hypoplasia, and absence of the corpus callosum. Some of the fetuses at later gestation showed microcystic dilatations of proximal kidney tubules and bile duct proliferation in the liver.

Laclef et al. (2015) had previously found that forebrain neuroepithelial cells of Rpgrip1l -/- mouse embryos had abnormal cilia devoid of axoneme. Rpgrip1l -/- telencephalon also showed severe ventrilization, which led to agenesis of olfactory bulbs and formation of ectopic olfactory bulb-like structures. Laclef et al. (2015) found that Rpgrip1l -/- guidepost and progenitor cells, which are involved in corpus callosum formation, also failed to form proper cilia. The coirticoseptal boundary in medial telencephalon of embryonic day-15.5 (E15.5) Rpgrip1l -/- embryos was severely perturbed, with cells of ventral identity present in the dorsal compartment and vice versa. Rpgrip1l -/- mutants also showed misexpression of several guidance molecules, including netrin-1 (NTN1; 601614) and Slit2 (603746). Patterning of commissural plate was already affected in E12.5 mutants. Reintroduction of the short repressor isoform of Gli3 (165240), Gli3r, restored normal telencephalic midline patterning and corpus collosum formation in the absence of primary cilia in Rpgrip1l -/- embryos.


ALLELIC VARIANTS 13 Selected Examples):

.0001   JOUBERT SYNDROME 7

RPGRIP1L, LYS233TER
SNP: rs121918197, gnomAD: rs121918197, ClinVar: RCV000001123, RCV000367935, RCV001385849, RCV001781156, RCV001831499

In a French patient with Joubert syndrome (JBTS7; 611560), Delous et al. (2007) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene: a 697A-T transversion in exon 6 resulting in a lys233-to-ter (K233X) substitution, and a T615P (610937.0002) mutation. The child had mental retardation, cerebellar ataxia, nephronophthisis, oculomotor apraxia, ptosis, and genu valgum. End-stage renal disease occurred at age 6 years.


.0002   JOUBERT SYNDROME 7

RPGRIP1L, THR615PRO
SNP: rs121918198, gnomAD: rs121918198, ClinVar: RCV000001124, RCV000393725, RCV000689745, RCV001271279, RCV002482812, RCV003155007, RCV003398408

In a French patient with Joubert syndrome (JBTS7; 611560), Delous et al. (2007) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene: a 1843A-C transversion in exon 15 of the RPGRIP1L gene resulting in a thr615-to-pro (T615P) substitution and a K233X (610937.0001) mutation. A second unrelated French patient with a similar phenotype was compound heterozygous for T615P and Q253X (610937.0003). Arts et al. (2007) found the T615P mutation in compound heterozygosity with a nonsense mutation (Q684X; 610937.0009) in a patient with Joubert syndrome.

Brancati et al. (2008) reported a brother and sister with Joubert syndrome who were homozygous for the T615P mutation. Both presented with developmental delay, growth and mental retardation, nephronophthisis, and severe scoliosis. Visual acuity, fundus examination, and liver function were normal. There was clinical variability between the 2 sibs regarding some features, with the sister being more severely affected. She died at age 17.5 years from renal failure, while he was still alive at age 22 years after kidney transplant. Both had the molar tooth sign on MRI.


.0003   JOUBERT SYNDROME 7

RPGRIP1L, GLN253TER
SNP: rs121918199, gnomAD: rs121918199, ClinVar: RCV000001125, RCV001067857, RCV001831500, RCV003398409

In a French patient with Joubert syndrome (JBTS7; 611560), Delous et al. (2007) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene: a 757C-T transition in exon 6 resulting in a gln253-to-ter (Q253X) substitution and a T615P (610937.0002) mutation. The patient had mental retardation, cerebellar ataxia, nephronophthisis, oculomotor apraxia, the molar tooth sign, ptosis, and scoliosis.


.0004   JOUBERT SYNDROME 7

RPGRIP1L, ALA695PRO
SNP: rs121918200, gnomAD: rs121918200, ClinVar: RCV000001126

In 2 French sibs with Joubert syndrome (JBTS7; 611560), Delous et al. (2007) identified a homozygous 2083G-C transversion in exon 15 of the RPGRIP1L gene, resulting in an ala695-to-pro (A695P) substitution. Both sibs had scoliosis, oculomotor apraxia, nystagmus, the molar tooth sign, and nephronophthisis with end-stage renal disease by age 9 years. Only 1 had mild mental retardation.


.0005   MECKEL SYNDROME, TYPE 5

RPGRIP1L, ARG132TER
SNP: rs121918201, ClinVar: RCV000001127, RCV001042174

In 2 presumably related Moroccan fetuses diagnosed with Meckel syndrome (MKS5; 611561) at 15 to 16 weeks' gestation by ultrasound, Delous et al. (2007) identified a homozygous 394A-T transversion in exon 4 of the RPGRIP1L gene, resulting in an arg132-to-ter (R132X) substitution. Post-termination examination showed anencephaly, occipital encephalocele, postaxial polydactyly, cleft lip and palate, microphthalmia, cystic kidney disease, and hepatic bile duct proliferation. One fetus showed bowing of the long bones. The severe phenotype corresponded to the complete loss of RPGRIP1L function.


.0006   MECKEL SYNDROME, TYPE 5

RPGRIP1L, GLN345TER
SNP: rs121918202, ClinVar: RCV000001128, RCV003764506

In a French fetus diagnosed with Meckel syndrome (MKS5; 611561) at 16 weeks' gestation by ultrasound, Delous et al. (2007) identified compound heterozygosity for 2 truncation mutations in the RPGRIP1L gene: a 1033C-T transition in exon 9 resulting in a gln345-to-ter (Q345X) substitution, and a 2614C-T transition in exon 17 resulting in a gln872-to-ter (Q872X; 610937.0007) substitution. Post-termination examination showed anencephaly, occipital encephalocele, postaxial polydactyly, cleft lip and palate, microphthalmia, cystic kidney disease, hepatic bile duct proliferation, and bowing of the long bones. The severe phenotype corresponded to the complete loss of RPGRIP1L function.


.0007   MECKEL SYNDROME, TYPE 5

RPGRIP1L, GLN872TER
SNP: rs121918203, gnomAD: rs121918203, ClinVar: RCV000033207, RCV000762961, RCV000779628, RCV000790748, RCV001059320, RCV001831501, RCV003894781

For discussion of the gln872-to-ter (Q872X) mutation in the RPGRIP1L gene that was found in compound heterozygous state in a fetus diagnosed with Meckel syndrome (MKS5; 611561) by Delous et al. (2007), see 610937.0006.


.0008   JOUBERT SYNDROME 7

RPGRIP1L, 1-BP DEL, 1721A
SNP: rs863225216, ClinVar: RCV000201652

In a Turkish girl with Joubert syndrome (JBTS7; 611560), born of consanguineous parents, Arts et al. (2007) identified a homozygous 1-bp deletion (1721delA) in the RPGRIP1L gene, resulting in a frameshift and premature protein truncation before the C2 domain. The 10-year-old girl had molar tooth sign, hypotonia, ataxia, mental retardation, abnormal eye movements, and renal disease. Retinal disease was not present.


.0009   JOUBERT SYNDROME 7

RPGRIP1L, GLN684TER
SNP: rs121918204, gnomAD: rs121918204, ClinVar: RCV000001131, RCV000762962, RCV000824619, RCV001271277, RCV001781157, RCV001813927

In a patient with Joubert syndrome (JBTS7; 611560), Arts et al. (2007) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene: a 2050C-T transition, resulting in a gln684-to-ter (Q684X) substitution, and a T615P (610937.0002) mutation. The Q684X mutation was predicted to truncate the protein before the C2 domain. In vitro functional expression studies showed that both mutant proteins disrupted NPHP4 binding. At age 5, the child had the molar tooth sign, hypotonia, ataxia, mental retardation, abnormal eye movements, postaxial polydactyly, and encephalocele. Renal and retinal disease were not present.


.0010   JOUBERT SYNDROME 7

RPGRIP1L, 1-BP DEL, 2268A
SNP: rs387906243, ClinVar: RCV000001132

In a Moroccan girl with Joubert syndrome (JBTS7;611560), born of consanguineous parents, Brancati et al. (2008) identified a homozygous 1-bp deletion (2268delA) in exon 16 of the RPGRIP1L gene, resulting in a frameshift and premature protein truncation. She had episodes of hyperpnea and apnea and delayed milestones. At age 1 year, she developed renal dysfunction associated with small kidneys with increased echogenicity, loss of corticomedullary differentiation, and multiple cysts compatible with nephronophthisis. At age 4 years, she had chronic renal failure, marked growth retardation, and severe psychomotor delay with lack of head control and inability to speak any meaningful words. The molar tooth sign was present on MRI.


.0011   COACH SYNDROME 3 (1 patient)

RPGRIP1L, ARG805TER
SNP: rs145665129, gnomAD: rs145665129, ClinVar: RCV000001134, RCV000201645, RCV000733537, RCV001382825, RCV001831502, RCV002490288

In a 17-year-old male with COACH syndrome-3 (COACH3; 619113), defined as Joubert syndrome with liver disease, Doherty et al. (2010) identified compound heterozygosity for 2 mutations in the RPGRIP1L gene: a 2413C-T transition, resulting in an arg805-to-ter (R805X) substitution, and a 1975T-C transition, resulting in a ser659-to-pro (S659P; 610937.0012) substitution. The patient had abnormal breathing pattern, mental retardation, molar tooth sign on brain MRI, congenital hepatic fibrosis with bile duct abnormalities, and nephronophthisis requiring renal transplant.


.0012   COACH SYNDROME 3 (1 patient)

RPGRIP1L, SER659PRO
SNP: rs267607020, gnomAD: rs267607020, ClinVar: RCV000001135, RCV000201757

For discussion of the ser659-to-pro (S659P) mutation in the RPGRIP1L gene that was found in compound heterozygous state in a patient with COACH syndrome-3 (COACH3; 619113) by Doherty et al. (2010), see 610937.0011.


.0013   RETINITIS PIGMENTOSA IN CILIOPATHIES, MODIFIER OF

RPGRIP1L, ALA229THR ({dbSNP rs61747071})
SNP: rs61747071, gnomAD: rs61747071, ClinVar: RCV000001133, RCV000035002, RCV000114223, RCV000234815, RCV000332989, RCV000473873, RCV001094311, RCV001094370, RCV001705578, RCV002293972

Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene, a 685G-A transition, resulting in an ala229-to-thr (A229T) substitution (rs61747071), may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations. The 229T allele was significantly enriched among a group of 487 patients with ciliopathy and retinal pigmentosa, including LCA (204000), Senior-Loken syndrome (266900), Joubert syndrome (213300), and BBS (209900), compared to 115 patients with ciliopathy without retinal pigmentosa, including NPHP (256100) and MKS (249000) (p = 1.66 x 10(-5)). In vitro functional expression studies showed that the 229T allele had decreased ability to bind to RPGR compared to the 229A allele.


REFERENCES

  1. Arts, H. H., Doherty, D., van Beersum, S. E. C., Parisi, M. A., Letteboer, S. J. F., Gorden, N. T., Peters, T. A., Marker, T., Voesenek, K., Kartono, A., Ozyurek, H., Farin, F. M., Kroes, H. Y., Wolfrum, U., Brunner, H. G., Cremers, F. P. M., Glass, I. A., Knoers, N. V. A. M., Roepman, R. Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nature Genet. 39: 882-888, 2007. [PubMed: 17558407] [Full Text: https://doi.org/10.1038/ng2069]

  2. Brancati, F., Travaglini, L., Zablocka, D., Boltshauser, E., Accorsi, P., Montagna, G., Silhavy, J. L., Barrano, G., Bertini, E., Emma, F., Rigoli, L., the International JSRD Study Group, Dallapiccola, B., Gleeson, J. G., Valente, E. M. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin. Genet. 74: 164-170, 2008. [PubMed: 18565097] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01047.x]

  3. Delous, M., Baala, L., Salomon, R., Laclef, C., Vierkotten, J., Tory, K., Golzio, C., Lacoste, T., Besse, L., Ozilou, C., Moutkine, I., Hellman, N. E., and 25 others. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nature Genet. 39: 875-881, 2007. [PubMed: 17558409] [Full Text: https://doi.org/10.1038/ng2039]

  4. Doherty, D., Parisi, M. A., Finn, L. S., Gunay-Aygun, M., Al-Mateen, M., Bates, D., Clericuzio, C., Demir, H., Dorschner, M., van Essen, A. J., Gahl, W. A., Gentile, M., and 11 others. Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J. Med. Genet. 47: 8-21, 2010. [PubMed: 19574260] [Full Text: https://doi.org/10.1136/jmg.2009.067249]

  5. Khanna, H., Davis, E. E., Murga-Zamalloa, C. A., Estrada-Cuzcano, A., Lopez, I., den Hollander, A. I., Zonneveld, M. N., Othman, M. I., Waseem, N., Chakarova, C. F., Maubaret, C., Diaz-Font, A., and 22 others. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nature Genet. 41: 739-745, 2009. [PubMed: 19430481] [Full Text: https://doi.org/10.1038/ng.366]

  6. Laclef, C., Anselme, I., Besse, L., Catala, M., Palmyre, A., Baas, D., Paschaki, M., Pedraza, M., Metin, C., Durand, B., Schneider-Maunoury, S. The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor. Hum. Molec. Genet. 24: 4997-5014, 2015. [PubMed: 26071364] [Full Text: https://doi.org/10.1093/hmg/ddv221]

  7. Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 63-70, 1999. [PubMed: 10231032] [Full Text: https://doi.org/10.1093/dnares/6.1.63]

  8. Williams, C. L., Li, C., Kida, K., Inglis, P. N., Mohan, S., Semenec, L., Bialas, N. J., Stupay, R. M., Chen, N., Blacque, O. E., Yoder, B. K., Leroux, M. R. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J. Cell. Biol. 192: 1023-1041, 2011. [PubMed: 21422230] [Full Text: https://doi.org/10.1083/jcb.201012116]

  9. Wolf, M. T. F., Saunier, S., O'Toole, J. F., Wanner, N., Groshong, T., Attanasio, M., Salomon, R., Stallmach, T., Sayer, J. A., Waldherr, R., Griebel, M., Oh, J., Neuhaus, T. J., Josefiak, U., Antignac, C., Otto, E. A., Hildebrandt, F. Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis. Kidney Int. 72: 1520-1526, 2007. [PubMed: 17960139] [Full Text: https://doi.org/10.1038/sj.ki.5002630]


Contributors:
Patricia A. Hartz - updated : 02/26/2016
Patricia A. Hartz - updated : 4/29/2011
Cassandra L. Kniffin - updated : 6/16/2010
Cassandra L. Kniffin - updated : 6/15/2009
Cassandra L. Kniffin - updated : 4/21/2009
Cassandra L. Kniffin - updated : 8/18/2008
Cassandra L. Kniffin - updated : 10/29/2007

Creation Date:
Patricia A. Hartz : 4/17/2007

Edit History:
carol : 12/01/2020
mgross : 02/26/2016
alopez : 4/22/2015
mcolton : 4/16/2015
carol : 1/18/2012
carol : 11/22/2011
mgross : 5/19/2011
mgross : 5/19/2011
terry : 4/29/2011
mgross : 4/28/2011
wwang : 6/24/2010
ckniffin : 6/16/2010
wwang : 6/18/2009
ckniffin : 6/15/2009
wwang : 4/30/2009
ckniffin : 4/21/2009
wwang : 8/25/2008
ckniffin : 8/18/2008
wwang : 11/16/2007
ckniffin : 10/29/2007
carol : 7/6/2007
mgross : 4/17/2007