Abstract
Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign’. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Brancati F, Dallapiccola B, Valente EM : Joubert Syndrome and related disorders. Orphanet J Rare Dis 2010; 5: 20.
Parisi M, Glass I Joubert Syndrome and Related Disorders: GeneReviewshttp://www.ncbi.nlm.nih.gov/books/NBK1325/ Initial Posting: 9 July 2003; Last Revision: 14 June 2012.
Srour M, Hamdan FF, Schwartzentruber JA et al: Mutation in TMEM231 cause Joubert Syndrome in French Canadians. J Med Genet 2012; 49: 636–641.
Novarino G, Akizu N, Gleeson JG : Modeling human disease in humans: the ciliopathies. Cell 2011; 147: 70–79.
Brancati F, Barrano G, Silhavy JL et al: CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. Am J Hum Genet 2007; 81: 104–113.
Brancati F, Iannicelli M, Travaglini L et al: MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement. Hum Mutat 2009; 30: E432–E442.
Castori M, Valente EM, Donati MA et al: NPHP1 gene deletion is a rare cause of Joubert syndrome related disorders. J Med Genet 2005; 42: e9.
Bachmann-Gagescu R, Ishak GE, Dempsey JC et al: Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures. J Med Genet 2012; 49: 126–137.
Doherty D, Parisi MA, Finn LS et al: Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J Med Genet 2010; 47: 8–21.
Jacoby M, Cox JJ, Gayral S et al: INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet 2009; 41: 1027–1031.
Bielas SL, Silhavy JL, Brancati F et al: Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet 2009; 41: 1032–1036.
Salonen R : The Meckel syndrome: clinicopathological findings in 67 patients. Am J Med Genet 1984; 18: 671–689.
Travaglini L, Brancati F, Attie-Bitach T et al: Expanding CEP290 mutational spectrum in ciliopathies. Am J Med Genet 2009; 149A: 2173–2180.
DePristo MA, Banks E, Poplin R et al: A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 2011; 43: 491–498.
Dyson JM, Fedele CG, Davies EM, Becanovic J, Mitchell CA : Phosphoinositide phosphatases: just as important as the kinases. Subcell Biochem 2012; 58: 215–279.
Cantagrel V, Silhavy JL, Bielas SL et al: Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Am J Hum Genet 2008; 83: 170–179.
Lee JE, Silhavy JL, Zaki MS et al: CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nat Genet 2012; 44: 193–199.
Valente EM, Brancati F, Silhavy JL et al: AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. Ann Neurol 2006; 59: 527–534.
Valente EM, Logan CV, Mougou-Zerelli S et al: Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet 2010; 42: 619–625.
Iannicelli M, Brancati F, Mougou-Zerelli S et al: Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies. Hum Mutat 2010; 31: E1319–E1331.
Arts HH, Doherty D, van Beersum SE et al: Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nat Genet 2007; 39: 882–888.
Khanna H, Davis EE, Murga-Zamalloa CA et al: A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nat Genet 2009; 41: 739–745.
Louie CM, Caridi G, Lopes VS et al: AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis. Nat Genet 2010; 42: 175–180.
Davis EE, Zhang Q, Liu Q et al: TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet 2011; 43: 189–196.
Katsanis N, Ansley SJ, Badano JL et al: Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science 2001; 293: 2256–2259.
Poretti A, Dietrich Alber F, Brancati F, Dallapiccola B, Valente EM, Boltshauser E : Normal cognitive functions in joubert syndrome. Neuropediatrics 2009; 40: 287–290.
Thomas S et al: TCTN3 mutations cause Mohr-Majewski syndrome. Am J Hum Genet 2012; 91: 372–378.
Chaki M et al: Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 2012; 150: 533–548.
Acknowledgements
This work was partly supported with grants from the Italian Ministry of Health (Ricerca Corrente 2012 to EMV, Ricerca Finalizzata 2009 to EB and EMV), the Italian Telethon Foundation (GGP08045 to EB and EMV), the European Research Council (Starting Grant 260888 to EMV), the National Institute of Health (R01NS048453 to JGG), the Broad Institute (U54HG003067 to Eric Lander) for sequencing support and analysis. We thank Dr Celine Gomes and Professor Arnold Munnich for referring patients.
Author information
Authors and Affiliations
Consortia
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Appendix
Appendix
Other members of the International JSRD Study Group are: L Ali Pacha (Alger, Algeria); A Zankl (Brisbane, Australia); R Leventer (Parkville, Australia); P Grattan-Smith (Sydney, Australia); A Janecke (Innsbruck, Austria); J Koch (Salzburg, Austria); M Freilinger (Vienna, Austria); M D’Hooghe (Brugge, Belgium); Y Sznajer, C Vilain (Bruxelles, Belgium); R Van Coster (Ghent, Belgium); L Demerleir (Brussels, Belgium); K Dias, C Moco, A Moreira (Porto Alegre, Brazil); C Ae Kim (Sao Paulo, Brazil); G Maegawa (Toronto, Canada); I Dakovic, D Loncarevic, V Mejaski-Bosnjak, D Petkovic (Zagreb, Croatia); GMH Abdel-Salam, A Abdel-Aleem, (Cairo, Egypt); I Marti, JM Pinard, S Quijano-Roy (Garches, France); S Sigaudy (Marseille, France); P de Lonlay, S Romano, A Verloes (Paris, France); R Touraine (St Etienne, France); M Koenig, H Dollfus, E Flori, M Fradin, C Lagier-Tourenne, J Messer (Strasbourg, France); P Collignon (Toulon, France); JM Penzien (Augsburg, Germany); C Bussmann (Heidelberg, Germany); A Merkenschlager (Leipzig, Germany); H Philippi (Mainz, Germany); G Kurlemann (Munster, Germany); K Grundmann (Tubingen, Germany); C Dacou-Voutetakis, S Kitsiou Tzeli, R Pons (Athens, Greece); J Jerney (Budapest, Hungary); S Halldorsson, J Johannsdottir, P Ludvigsson (Reykjavik, Iceland); SR Phadke (Lucknow, India); KM Girisha (Manipal, India); H Doshi, V Udani (Mumbay, India); M Kaul (Rajkot, India); B Stuart (Dublin, Ireland); A Magee (Belfast, Northern Ireland); R Spiegel, S Shalev (Afula, Israel); H Mandel (Haifa, Israel); D Lev, M Michelson (Holon, Israel); M Idit (Petach-Tikva, Israel); B Ben-Zeev (Ramat-Gan, Israel); R Gershoni-Baruch (Rambam, Israel); A Ficcadenti (Ancona, Italy); R Fischetto, M Gentile (Bari, Italy); M Della Monica (Benevento, Italy); M Pezzani (Bergamo, Italy); C Graziano, M Seri (Bologna); F Benedicenti, F Stanzial (Bolzano, Italy); R Borgatti, R Romaniello (Bosisio Parini, Italy); P Accorsi, S Battaglia, E Fazzi, L Giordano, L Pinelli (Brescia, Italy); L Boccone (Cagliari, Italy); R Barone, G Sorge (Catania, Italy); E Briatore (Cuneo, Italy); S Bigoni, A Ferlini (Ferrara, Italy); MA Donati (Florence, Italy); R Biancheri, G Caridi, MT Divizia, F Faravelli, G Ghiggeri, M Mirabelli, A Pessagno, A Rossi, V Uliana (Genoa, Italy); M Amorini, M Briguglio, S Briuglia, CD Salpietro, G Tortorella (Messina, Italy); A Adami, MT Bonati, P Castorina, S D’Arrigo, F Lalatta, G Marra, I Moroni, C Pantaleoni, D Riva, B Scelsa, L Spaccini (Milan, Italy); E Del Giudice (Napoli, Italy); K Ludwig, A Permunian, A Suppiej (Padova, Italy); C Macaluso (Parma, Italy); A Pichiecchio (Pavia, Italy); R Battini (Pisa, Italy); M Di Giacomo (Potenza, Italy); M Priolo, P Timpani (Reggio Calabria, Italy); G Pagani (Rho, Italy); ML Di Sabato, F Emma, V Leuzzi, F Mancini, S Majore, A Micalizzi, P Parisi, M Romani, G Stringini, G Zanni (Rome, Italy); L Ulgheri (Sassari, Italy); M Pollazzon, A Renieri (Siena, Italy); E Belligni, E Grosso, I Pieri, M Silengo (Torino, Italy); R Devescovi (Trieste, Italy); D Greco, C Romano (Troina, Italy); M Cazzagon (Udine, Italy); A Simonati (Verona, Italy); AA Al-Tawari, L Bastaki, (Kuwait City, Kuwait); A Mégarbané (Beirut, Lebanon); V Sabolic Avramovska (Skopje, Macedonia); E Said (Msida, Malta); P Stromme (Oslo, Norway); R Koul, A Rajab (Muscat, Oman); M Azam (Islamabad, Pakistan); C Barbot (Oporto, Portugal); MA Salih, B Tabarki (Riyadh, Saudi Arabia); B Jocic-Jakubi (Nis, Serbia); L Martorell Sampol (Barcelona, Spain); B Rodriguez (La Coruna, Spain); I Pascual-Castroviejo (Madrid, Spain); B Gener (Vizcaya, Spain); A Puschmann (Lund, Sweden); L Starck (Stockholm, Sweden); A Capone (Aarau, Switzerland); J Lemke (Bern, Switzerland); J Fluss (Geneva, Switzerland); D Niedrist (Zurich, Switzerland); RCM Hennekam, N Wolf (Amsterdam, The Netherlands); N Gouider-Khouja, I Kraoua (Tunis, Tunisia); S Ceylaner, S Teber (Ankara, Turkey); M Akgul (Izmir, Turkey); B Anlar, S Comu, H Kayserili, A Yüksel (Istanbul, Turkey); M Akcakus, AO Caglayan (Kayseri, Turkey); O Aldemir (Mersin, Turkey); L Al Gazali, L Sztriha (Al Ain, UAE); D Nicholl (Birmingham, UK); CG Woods (Cambridge, UK); C Bennett, J Hurst, E Sheridan (Leeds, UK); A Barnicoat, C Hemingway, M Lees, E Wakeling (London, UK); E Blair (Oxford, UK); S Bernes (Mesa, Arizona, USA); H Sanchez (Fremont, California, USA); AE Clark (Laguna Niguel, California, USA); E DeMarco, C Donahue, E Sherr (San Francisco, California, USA); J Hahn, TD Sanger (Stanford California, USA); TE Gallager (Manoa, Hawaii, USA); C Daugherty (Bangor, Maine, USA); KS Krishnamoorthy, D Sarco, CA Walsh (Boston, Massachusetts, USA); T McKanna (Grand Rapids, Michigan, USA); J Milisa (Albuquerque, New Mexico, USA); WK Chung, DC De Vivo, H Raynes, R Schubert (New York, New York, USA); A Seward (Columbus, Ohio, USA); DG Brooks (Philadephia, Pennsylvania, USA); A Goldstein (Pittsburg, Pennsylvania, USA); J Caldwell, E Finsecke (Tulsa, Oklahoma, USA); BL Maria (Charleston, South Carolina, USA), K Holden (Mt. Pleasant, South Carolina, USA); RP Cruse, E Karaca (Houston, Texas, USA); KJ Swoboda, D Viskochil (Salt Lake City, Utah, USA), WB Dobyns (Seattle, Washington, USA).
Rights and permissions
About this article
Cite this article
Travaglini, L., Brancati, F., Silhavy, J. et al. Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders. Eur J Hum Genet 21, 1074–1078 (2013). https://doi.org/10.1038/ejhg.2012.305
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2012.305
Keywords
This article is cited by
-
Inpp5e Regulated the Cilium-Related Genes Contributing to the Neural Tube Defects Under 5-Fluorouracil Exposure
Molecular Neurobiology (2024)
-
Skeletal ciliopathy: pathogenesis and related signaling pathways
Molecular and Cellular Biochemistry (2023)
-
Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD
npj Genomic Medicine (2021)
-
Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development
BMC Developmental Biology (2020)
-
Detecting TF-miRNA-gene network based modules for 5hmC and 5mC brain samples: a intra- and inter-species case-study between human and rhesus
BMC Genetics (2018)
