.. _RPGRIP1L:

RPGRIP1L
^^^^^^^^

.. contents::
   :local:

General Information
*******************

:Full gene name: RPGRIP1-like
:Entrez Gene ID: 23322
:Location: 16q12.2
:Synonyms: NPHP8, MKS5, JBTS7, FTM, CORS3
:Type: protein-coding

User SNPs
*********

SNPs given by the user that are near or inside this gene: 

+-----------+---------------+-----------+
|    SNP    | Distance (bp) | Direction |
+===========+===============+===========+
| rs9939609 |     82756     |  upstream |
+-----------+---------------+-----------+

.. _RPGRIP1L Gene summary:

NCBI Summary
************

The protein encoded by this gene can localize to the basal body-centrosome complex or to primary cilia and centrosomes in ciliated cells. The encoded protein has been found to interact with nephrocystin-4. Defects in this gene are a cause of Joubert syndrome type 7 (JBTS7) and Meckel syndrome type 5 (MKS5). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

.. _OMIM ID 610937
                        : http://omim.org/entry/610937
                        

.. _RPGRIP1L OMIM Text:

OMIM
****

:OMIM ID: `OMIM ID 610937
                        `_

**Allelic Variants (Selected Examples)**

.0001 JOUBERT SYNDROME 7

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

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).

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

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

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

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

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

See 610937.0006 and Delous et al. (2007).

.0008 JOUBERT SYNDROME 7

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

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

In a Moroccan girl with Joubert syndrome (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 word. The molar tooth sign was present on MRI.

.0011 COACH SYNDROME

In a 17-year-old male with COACH syndrome (216360), defined as Joubert syndrome (611560) with liver involvement, 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 dule abnormalities, and nephronophthisis requiring renal transplant.

.0012 COACH SYNDROME

See 610937.0011 and Doherty et al. (2010).

.0013 RETINITIS PIGMENTOSA IN CILIOPATHIES, MODIFIER OF

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.




.. _RPGRIP1L Phenotype:

NCBI Phenotypes
***************

* Gene Reviews
* Propensity score-based nonparametric test revealing genetic variants underlying bipolar disorder.
* OMIM
* GTR
* Joubert syndrome 7
* Nephronophthisis 8
* COACH syndrome
* Meckel syndrome, type 5
* NHGRI GWA Catalog

.. _RPGRIP1L GO Term:

Gene Ontology
*************

* pericardium development
* cytoplasm
* cilium axoneme
* olfactory bulb development
* tight junction
* microtubule basal body
* protein binding
* lateral ventricle development
* regulation of smoothened signaling pathway
* determination of left/right symmetry
* in utero embryonic development
* cilium assembly
* embryonic forelimb morphogenesis
* cell-cell junction
* neural tube patterning
* liver development
* negative regulation of G-protein coupled receptor protein signaling pathway
* head development
* corpus callosum development
* centrosome
* thromboxane A2 receptor binding
* nose development
* camera-type eye development
* cerebellum development
* kidney development
* embryonic hindlimb morphogenesis
* cilium

.. _RPGRIP1L Pathway:

KEGG Pathways
*************

No pathways found linked to this gene.

.. _RPGRIP1L GeneRIF:

GeneRIFs
********

* RPGRIP1L mutations are largely confined to the cerebello-renal subgroup, while they overall represent a rare cause of JSRD (<2%). [`PMID 18565097`_]
* Mutations can cause the multiorgan phenotypic abnormalities found in cerebello-oculo-renal syndrome or Meckel syndrome. [`PMID 17558409`_]
* CSPP isoforms require their common C-terminal domain to interact with Nephrocystin 8 (NPHP8/RPGRIP1L) and to form a ternary complex with NPHP8 and NPHP4. [`PMID 20519441`_]
* Mutations in RPGRIP1L: extending the clinical spectrum of ciliopathies. Review. [`PMID 18281315`_]
* data suggest that RPGRIP1L suppresses anchorage-independent growth partly through the mitotic checkpoint protein Mad2. [`PMID 19410446`_]
* Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L. [`PMID 19574260`_]
* \ ``Insulin``\  was identified as a key factor regulating FTM expression during human preadipocyte differentiation. [`PMID 20865646`_]
* Nek4 interaction with both RPGRIP1 and the RPGRIP1L is involved in cilium assembly. [`PMID 21685204`_]
* Discuss Fto/Ftm gene expression regulation via CUTL1. [`PMID 18256137`_]
* Observational study of gene-disease association. (HuGE Navigator) [`PMID 21068128`_]
* Responsible for Joubert syndrome, affecting cilia and basal bodies. [`PMID 17558407`_]
* Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [`PMID 20628086`_]
* T615P mutation represents the most common mutation in the RPGRIP1L gene causing disease in about 8-10% of Joubert syndrome type B patients negative for NPHP1, NPHP6, or AHI1 mutations [`PMID 17960139`_]
* Affinity Capture-MS [`PMID 21139048`_]
* First evidence of the association between RPGRIP1L gene and susceptibility of Vascular Dementia. [`PMID 22425971`_]
* RPGRIP1L interacts with retinitis pigmentosa GTPase, loss of which causes retinal degeneration. [`PMID 19430481`_]
* Observational study and meta-analysis of gene-disease association. (HuGE Navigator) [`PMID 18426861`_]
* Genetic variation may affect severity of disease for X-linked retinitis pigmentosa. [`PMID 22183348`_]
* Data show that the minor allele (N) of I393N in IQCB1 and the common allele (R) of R744Q in RPGRIP1L were associated with severe disease in XlRP with RPGR mutations. [`PMID 21857984`_]

.. _PMID 18565097: http://www.ncbi.nlm.nih.gov/pubmed/18565097
.. _PMID 17558409: http://www.ncbi.nlm.nih.gov/pubmed/17558409
.. _PMID 20519441: http://www.ncbi.nlm.nih.gov/pubmed/20519441
.. _PMID 18281315: http://www.ncbi.nlm.nih.gov/pubmed/18281315
.. _PMID 19410446: http://www.ncbi.nlm.nih.gov/pubmed/19410446
.. _PMID 19574260: http://www.ncbi.nlm.nih.gov/pubmed/19574260
.. _PMID 20865646: http://www.ncbi.nlm.nih.gov/pubmed/20865646
.. _PMID 21685204: http://www.ncbi.nlm.nih.gov/pubmed/21685204
.. _PMID 18256137: http://www.ncbi.nlm.nih.gov/pubmed/18256137
.. _PMID 21068128: http://www.ncbi.nlm.nih.gov/pubmed/21068128
.. _PMID 17558407: http://www.ncbi.nlm.nih.gov/pubmed/17558407
.. _PMID 20628086: http://www.ncbi.nlm.nih.gov/pubmed/20628086
.. _PMID 17960139: http://www.ncbi.nlm.nih.gov/pubmed/17960139
.. _PMID 21139048: http://www.ncbi.nlm.nih.gov/pubmed/21139048
.. _PMID 22425971: http://www.ncbi.nlm.nih.gov/pubmed/22425971
.. _PMID 19430481: http://www.ncbi.nlm.nih.gov/pubmed/19430481
.. _PMID 18426861: http://www.ncbi.nlm.nih.gov/pubmed/18426861
.. _PMID 22183348: http://www.ncbi.nlm.nih.gov/pubmed/22183348
.. _PMID 21857984: http://www.ncbi.nlm.nih.gov/pubmed/21857984

.. _RPGRIP1L Pubmed:

PubMed Articles
***************

*Recent articles:*

* Woo J et al. "Genetic association of the gene encoding RPGRIP1L with susceptibility to vascular dementia." Gene. 2012 May 10;499(1):160-2. `PMID 22425971`_
* Fahim AT et al. "Polymorphic variation of RPGRIP1L and IQCB1 as modifiers of X-linked retinitis pigmentosa caused by mutations in RPGR." Adv Exp Med Biol. 2012;723:313-20. `PMID 22183348`_
* Coene KL et al. "The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase." Hum Mol Genet. 2011 Sep 15;20(18):3592-605. `PMID 21685204`_
* Fahim AT et al. "Allelic heterogeneity and genetic modifier loci contribute to clinical variation in males with X-linked retinitis pigmentosa due to RPGR mutations." PLoS One. 2011;6(8):e23021. `PMID 21857984`_
* Danielsen JM et al. "Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level." Mol Cell Proteomics. 2011 Mar;10(3):M110.003590. `PMID 21139048`_
* Otto EA et al. "Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy." J Med Genet. 2011 Feb;48(2):105-16. `PMID 21068128`_
* Jiang Y et al. "Propensity score-based nonparametric test revealing genetic variants underlying bipolar disorder." Genet Epidemiol. 2011 Feb;35(2):125-32. `PMID 21254220`_
* Tews D et al. "Regulation of FTO and FTM expression during human preadipocyte differentiation." Horm Metab Res. 2011 Jan;43(1):17-21. `PMID 20865646`_
* Bailey SD et al. "Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study." Diabetes Care. 2010 Oct;33(10):2250-3. `PMID 20628086`_
* Patzke S et al. "CSPP is a ciliary protein interacting with Nephrocystin 8 and required for cilia formation." Mol Biol Cell. 2010 Aug 1;21(15):2555-67. `PMID 20519441`_

.. _PMID 21139048: http://www.ncbi.nlm.nih.gov/pubmed/21139048
.. _PMID 20519441: http://www.ncbi.nlm.nih.gov/pubmed/20519441
.. _PMID 20865646: http://www.ncbi.nlm.nih.gov/pubmed/20865646
.. _PMID 21685204: http://www.ncbi.nlm.nih.gov/pubmed/21685204
.. _PMID 21068128: http://www.ncbi.nlm.nih.gov/pubmed/21068128
.. _PMID 21254220: http://www.ncbi.nlm.nih.gov/pubmed/21254220
.. _PMID 20628086: http://www.ncbi.nlm.nih.gov/pubmed/20628086
.. _PMID 22425971: http://www.ncbi.nlm.nih.gov/pubmed/22425971
.. _PMID 22183348: http://www.ncbi.nlm.nih.gov/pubmed/22183348
.. _PMID 21857984: http://www.ncbi.nlm.nih.gov/pubmed/21857984

*Top Pubmed articles linked to gene RPGRIP1L matching any search term:* 

* Stratigopoulos G et al. "Cut-like homeobox 1 (CUX1) regulates expression of the fat mass and obesity-associated and retinitis pigmentosa GTPase regulator-interacting protein-1-like (RPGRIP1L) genes and coordinates leptin receptor signaling." J Biol Chem. 2011 Jan 21;286(3):2155-70. `PMID 21037323`_
* Tews D et al. "Regulation of FTO and FTM expression during human preadipocyte differentiation." Horm Metab Res. 2011 Jan;43(1):17-21. `PMID 20865646`_
* Bailey SD et al. "Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study." Diabetes Care. 2010 Oct;33(10):2250-3. `PMID 20628086`_
* Berulava T et al. "The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels." Eur J Hum Genet. 2010 Sep;18(9):1054-6. `PMID 20512162`_
* Chang YC et al. "Common variation in the fat mass and obesity-associated (FTO) gene confers risk of obesity and modulates BMI in the Chinese population." Diabetes. 2008 Aug;57(8):2245-52. `PMID 18487448`_
* Qu HQ et al. "Association analysis of type 2 diabetes Loci in type 1 diabetes." Diabetes. 2008 Jul;57(7):1983-6. `PMID 18426861`_
* Klöting N et al. "Inverse relationship between obesity and FTO gene expression in visceral adipose tissue in humans." Diabetologia. 2008 Apr;51(4):641-7. `PMID 18251005`_
* Stratigopoulos G et al. "Regulation of Fto/Ftm gene expression in mice and humans." Am J Physiol Regul Integr Comp Physiol. 2008 Apr;294(4):R1185-96. `PMID 18256137`_

.. _PMID 18251005: http://www.ncbi.nlm.nih.gov/pubmed/18251005
.. _PMID 20865646: http://www.ncbi.nlm.nih.gov/pubmed/20865646
.. _PMID 18256137: http://www.ncbi.nlm.nih.gov/pubmed/18256137
.. _PMID 21037323: http://www.ncbi.nlm.nih.gov/pubmed/21037323
.. _PMID 20628086: http://www.ncbi.nlm.nih.gov/pubmed/20628086
.. _PMID 18487448: http://www.ncbi.nlm.nih.gov/pubmed/18487448
.. _PMID 18426861: http://www.ncbi.nlm.nih.gov/pubmed/18426861
.. _PMID 20512162: http://www.ncbi.nlm.nih.gov/pubmed/20512162