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Genetic complexity in Joubert syndrome and related disorders

2007; Elsevier BV; Volume: 72; Issue: 12 Linguagem: Inglês

10.1038/sj.ki.5002577

1523-1755

Peter C. Harris,

Congenital Anomalies and Fetal Surgery

The recent identification of RPGRIP1L as a Joubert syndrome gene brings the total of known genes to five. Three of these are also associated with the lethal Meckel syndrome, and two with Senior–Løken syndrome; both of these disorders share Joubert syndrome phenotypes, illustrating the genetic complexity of this. The recent identification of RPGRIP1L as a Joubert syndrome gene brings the total of known genes to five. Three of these are also associated with the lethal Meckel syndrome, and two with Senior–Løken syndrome; both of these disorders share Joubert syndrome phenotypes, illustrating the genetic complexity of this. Joubert syndrome is an autosomal recessive disorder characterized by cerebellar vermis hypoplasia, recognized by a distinctive brainstem malformation, the ‘molar tooth sign’ seen radiologically; abnormal eye movements; hypotonia; and development delay/mental retardation. Around a quarter of patients also have nephronophthisis (NPHP, consisting of tubulointerstitial fibrosis and cysts at the corticomedullary junction) and retinal dystrophy, which is termed Joubert syndrome type B, or cerebello-oculo-renal syndrome (CORS). A number of other clinical abnormalities are found in Joubert syndrome and related disorders (JSRD), including occipital encephalocele, polymicrogyria, cystic kidneys, polydactyly, hepatic fibrosis, and ocular coloboma. Several of these phenotypes are similar to those associated with the lethal, recessive disorder Meckel syndrome (MKS), which is characterized by renal cystic dysplasia, occipital encephalocele (or other central nervous system phenotypes), polydactyly, and hepatic fibrosis. A group of related disorders is recessively inherited isolated NPHP with an infantile, juvenile, or adolescent time at end-stage renal disease, which can also be associated with retinitis pigmentosa (Senior–Løken syndrome; SLS). Positional cloning studies in the past few years have revealed considerable genetic heterogeneity and genetic relatedness of these diseases. Joubert syndrome has an approximately described incidence in the United States of 1 in 100,000, and five gene loci have been described: AHI1 (6q23.3),1.Ferland R.J. Eyaid W. Collura R.V. et al.Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.Nat Genet. 2004; 36: 1008-1013Crossref PubMed Scopus (307) Google Scholar NPHP1 (2q13),2.Parisi M.A. Bennett C.L. Eckert M.L. et al.The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome.Am J Hum Genet. 2004; 75: 82-91Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar CEP290/NPHP6 (12q21.3),3.Sayer J.A. Otto E.A. O'Toole J.F. et al.The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.Nat Genet. 2006; 38: 674-681Crossref PubMed Scopus (423) Google Scholar MKS3 (8q22.1),4.Baala L. Romano S. Khaddour R. et al.The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.Am J Hum Genet. 2007; 80: 186-194Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar and RPGRIP1L (16q12.2),5.Delous M. Baala L. Salomon R. et al.The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome.Nat Genet. 2007; 39: 875-881Crossref PubMed Scopus (341) Google Scholar,6.Arts H.H. Doherty D. van Beersum S.E. et al.Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.Nat Genet. 2007; 39: 882-888Crossref PubMed Scopus (245) Google Scholar (Table 1) with two others linked to chromosome regions (9q34 and 11q2–q13) but not identified. The high level of genetic heterogeneity is similar to that of NPHP (seven genes identified) and MKS (four genes identified). AHI1 is thought to account for 10%–15% of cases of JSRD, and CEP290 is estimated to cause a similar proportion of such cases. Homozygous deletion of NPHP1 is responsible for 1%–2% of JSRD, and one study found MKS3 mutations in 4 of 22 JSRD patients.4.Baala L. Romano S. Khaddour R. et al.The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.Am J Hum Genet. 2007; 80: 186-194Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar RPGRIP1L is the most recently identified JSRD (CORS) gene that was recognized by two separate groups.5.Delous M. Baala L. Salomon R. et al.The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome.Nat Genet. 2007; 39: 875-881Crossref PubMed Scopus (341) Google Scholar,6.Arts H.H. Doherty D. van Beersum S.E. et al.Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.Nat Genet. 2007; 39: 882-888Crossref PubMed Scopus (245) Google Scholar Both used a genome-wide single-nucleotide polymorphism array linkage approach in consanguineous families and found a region of homozygosity on 16q that contained a good candidate on the basis of functional data (see below). This interval was syntenic with the mouse model Fused toes (Ft). Ft/Ft embryos die at mid-gestation with exencephaly, polydactyly, and laterality defects.5.Delous M. Baala L. Salomon R. et al.The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome.Nat Genet. 2007; 39: 875-881Crossref PubMed Scopus (341) Google Scholar, 7.Grotewold L. Ruther U. The Fused toes (Ft) mouse mutation causes anteroposterior and dorsoventral polydactyly.Dev Biol. 2002; 251: 129-141Crossref PubMed Scopus (17) Google Scholar, 8.Anselme I. Laclef C. Lanaud M. et al.Defects in brain patterning and head morphogenesis in the mouse mutant Fused toes.Dev Biol. 2007; 304: 208-220Crossref PubMed Scopus (48) Google Scholar These initial studies found mutations in nine JSRD families. Wolf and colleagues9.Wolf M.T.F. Saunier S. O'Toole J.F. et al.Mutational analysis of RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis.Kidney Int. 2007; 72: 1520-1526Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar (this issue) have now extended the mutation analysis of that locus in Joubert syndrome type B patients (negative for AHI1 and CEP290 mutations), and 5 of 56 had RPGRIP1L mutations. Two new cases were homozygous for a previously defined missense change, T615P, and one homozygous for a novel change, C633R. In two further cases, just one likely mutation was found, a typical splicing change, IVS23-2A→G or the missense change E393K. Overall, these studies show that RPGRIP1L is a significant cause of JSRD.Table 1Details of Joubert syndrome and related disorders (JSRD) genes and proteinsGeneJoubert syndrome phenotypeaMajor phenotypes detected: CVH, cerebellar vermis hypoplasia; DPM, ductal plate malformation; LCA, Leber congenital amaurosis; RM, renal microcysts; MKS, Meckel syndrome; MR, mental retardation/development delay; NPHP, nephronophthisis; OMA, ocular motor apraxia; RD, retinal dystrophy.Other disease associationsProtein locationNPHP1CVH, NPHP, OMANPHP, SLSCell–cell/matrixAHI1CVH, RD?CEP290MR, NPHP, LCASLS, NPHP, MKSCentrosome/ciliaMKS3CVH, MR, RM, DPMMKSCilia/basal body/centrosomeRPGRIP1LCVH, MR, NPHP, OMAMKSBasal body/ciliaa Major phenotypes detected: CVH, cerebellar vermis hypoplasia; DPM, ductal plate malformation; LCA, Leber congenital amaurosis; RM, renal microcysts; MKS, Meckel syndrome; MR, mental retardation/development delay; NPHP, nephronophthisis; OMA, ocular motor apraxia; RD, retinal dystrophy. Open table in a new tab The RPGRIP1L protein has been localized to the basal body-centrosome and ciliary axoneme and colocalized with the NPHP proteins NPHP4 and NPHP6.5.Delous M. Baala L. Salomon R. et al.The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome.Nat Genet. 2007; 39: 875-881Crossref PubMed Scopus (341) Google Scholar,6.Arts H.H. Doherty D. van Beersum S.E. et al.Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.Nat Genet. 2007; 39: 882-888Crossref PubMed Scopus (245) Google Scholar RPGRIP1L is a homologue of the retinitis pigmentosa GTPase regulator-interacting protein, RPGRIP1, which is a cause of Leber congenital amaurosis.10.Dryja T.P. Adams S.M. Grimsby J.L. et al.Null RPGRIP1 alleles in patients with Leber congenital amaurosis.Am J Hum Genet. 2001; 68: 1295-1298Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar RPGRIP1 has been localized to the connecting cilium of photoreceptors and also interacts with NPHP4 through a protein kinase C conserved region (C2 domain) that is 52% identical to that found in RPGRIP1L.11.Roepman R. Letteboer S.J. Arts H.H. et al.Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations.Proc Natl Acad Sci USA. 2005; 102: 18520-18525Crossref PubMed Scopus (101) Google Scholar RPGRIP1L consists of five coiled-coil domains in the N-terminal part of the protein, a C-terminal region with homology to the RPGR-interacting domain, and two central C2 domains. It appears to be widely expressed in the organs involved in JSRD. A common feature of proteins involved in JSRD, NPHP, MKS, the related Bardet–Biedl syndrome (which involves vision loss, mental retardation, renal disease, polydactyly, and obesity), and orofaciodigital (craniofacial abnormalities, polydactyly, and polycystic kidney disease) is the localization of causative proteins to the basal body-centrosome and in some cases to the axoneme of the cilium.12.Hildebrandt F. Zhou W. Nephronophthisis-associated ciliopathies.J Am Soc Nephrol. 2007; 18: 1855-1871Crossref PubMed Scopus (261) Google Scholar, 13.Parisi M.A. Doherty D. Chance P.F. Glass I.A. Joubert syndrome (and related disorders) (OMIM 213300).Eur J Hum Genet. 2007; 15: 511-521Crossref PubMed Scopus (149) Google Scholar, 14.Badano J.L. Mitsuma N. Beales P.L. Katsanis N. The ciliopathies: an emerging class of human genetic disorders.Annu Rev Genomics Hum Genet. 2006; 7: 125-148Crossref PubMed Scopus (843) Google Scholar The pleiotropic phenotypes associated with this collection of diseases are thought to be due to defective ciliary function and hence have been classed as ciliopathies. Primary cilia are thought to play an important sensory and mechanosensory role that links external cues to maintenance of the normal cellular differentiated state. Mechanosensation through the autosomal dominant polycystic kidney disease (ADPKD) protein (polycystin) complex is thought to be important for maintaining tubular differentiation in the kidney and liver, and defective cilia in the photoreceptor cells or the embryonic node result in retinal defects or laterality defects, respectively. Recently, important developmental pathways such as Hedgehog signaling and the non-canonical Wnt pathway have been linked with cilia and may underlie many of the development abnormalities (for example, polydactyly and exencephaly) associated with these disorders.15.Singla V. Reiter J.F. The primary cilium as the cell's antenna: signaling at a sensory organelle.Science. 2006; 313: 629-633Crossref PubMed Scopus (777) Google Scholar Recently, a downstream effector of the Hedgehog pathway, GLIS2, was found to be defective in NPHP.16.Attanasio M. Uhlenhaut N.H. Sousa V.H. et al.Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis.Nat Genet. 2007; 39: 1018-1024Crossref PubMed Scopus (164) Google Scholar The phenotypic overlap between JSRD and NPHP and MKS is reflected in the overlap of the genes that have been identified in these disorders. In three cases, CEP290, MKS3, and RPGRIP1L, genes associated with JSRD are also found in patients with the lethal MKS.5.Delous M. Baala L. Salomon R. et al.The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome.Nat Genet. 2007; 39: 875-881Crossref PubMed Scopus (341) Google Scholar, 17.Smith U.M. Consugar M. Tee L.J. et al.The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat.Nat Genet. 2006; 38: 191-196Crossref PubMed Scopus (202) Google Scholar, 18.Baala L. Audollent S. Martinovic J. et al.Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome.Am J Hum Genet. 2007; 81: 170-179Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 19.Frank V. den Hollander A.I. Bruchle N.O. et al.Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber sydrome.Hum Mutat. 2007; (Epub 17 August 2007. doi:10.1002/humu.20614)Google Scholar Likewise, two JSRD genes, NPHP1 and CEP290, are also associated with isolated NPHP and SLS.19.Frank V. den Hollander A.I. Bruchle N.O. et al.Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber sydrome.Hum Mutat. 2007; (Epub 17 August 2007. doi:10.1002/humu.20614)Google Scholar,20.Helou J. Otto E.A. Attanasio M. et al.Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior–Løken syndrome.J Med Genet. 2007; 44: 657-663Crossref PubMed Scopus (73) Google Scholar Allelic effects may be important for the severity of the phenotype, as a tendency for two probably inactivating mutations in MKS3 and RPGRIP1L is associated with MKS, and at least one possible hypomorphic allele (a missense change or atypical splicing event) is often found in patients with JSRD.4.Baala L. Romano S. Khaddour R. et al.The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.Am J Hum Genet. 2007; 80: 186-194Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar,9.Wolf M.T.F. Saunier S. O'Toole J.F. et al.Mutational analysis of RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis.Kidney Int. 2007; 72: 1520-1526Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar However, this tendency does not explain all of the phenotypic penetrance, as a homozygous deletion (1721delA) and a homozygous typical splicing change (2305-1G→A) to RPGRIP1L are associated with a viable JSRD phenotype.6.Arts H.H. Doherty D. van Beersum S.E. et al.Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.Nat Genet. 2007; 39: 882-888Crossref PubMed Scopus (245) Google Scholar In the case of CEP290, allelic effects seem less compelling, since many cases with two apparent truncating mutations are associated with a viable phenotype,20.Helou J. Otto E.A. Attanasio M. et al.Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior–Løken syndrome.J Med Genet. 2007; 44: 657-663Crossref PubMed Scopus (73) Google Scholar as well as with MKS,18.Baala L. Audollent S. Martinovic J. et al.Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome.Am J Hum Genet. 2007; 81: 170-179Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar,19.Frank V. den Hollander A.I. Bruchle N.O. et al.Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber sydrome.Hum Mutat. 2007; (Epub 17 August 2007. doi:10.1002/humu.20614)Google Scholar which indicates that other genetic (and environmental) factors are also probably influencing the phenotype. In several cases of JSRD associated with RPGRIP1L or CEP290 mutation, only a single likely mutation has been identified.9.Wolf M.T.F. Saunier S. O'Toole J.F. et al.Mutational analysis of RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis.Kidney Int. 2007; 72: 1520-1526Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar,20.Helou J. Otto E.A. Attanasio M. et al.Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior–Løken syndrome.J Med Genet. 2007; 44: 657-663Crossref PubMed Scopus (73) Google Scholar This may simply reflect missed mutations that are not detected by the typical screen for base-pair changes in exonic regions. However, it suggests that oligogenic inheritance may also play a role in this disorder. In the highly genetically heterozygous Bardet–Biedl syndrome, oligogenic inheritance, with mutations involving more than one gene and the involvement of three mutant alleles, is important in some cases for disease development22.Beales P.L. Badano J.L. Ross A.J. et al.Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome.Am J Hum Genet. 2003; 72: 1187-1199Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar,23.Badano J.L. Kim J.C. Hoskins B.E. et al.Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.Hum Mol Genet. 2003; 12: 1651-1659Crossref PubMed Scopus (151) Google Scholar and has also recently been described in NPHP. 24.Hoefele J. Wolf M.T. O'Toole J.F. et al.Evidence of oligogenic inheritance in nephronophthisis.J Am Soc Nephrol. 2007; 18: 2789-2795Crossref PubMed Scopus (108) Google Scholar The increasing number of JSRD genes, the variable phenotype only partly associated with genic and allelic effects, plus cases with missing mutations, indicate that this step toward complex inheritance is also a possibility in JSRD. The overlapping phenotypes of JSRD, MKS, NPHP, and SLS, plus the overlapping group of genes involved in causing these diseases, highlight deficiencies in the existing forms of disease classification. Although the phenotypic description of a family is clearly what initially determines the disease classification and focuses the search for the molecular cause, it is limited as a final disease classifier. Increasingly, it will be important to base the disease classification on the gene that is mutated. Although this is complicated by allelic effects, genetic background, and possible other complex inheritance, it is the most logical basis for classifying genetic diseases and an essential starting point for comprehensive genotype–phenotype studies.