Abstract
Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic “molar tooth sign” on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients’ fibroblasts.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. doi:10.1038/nmeth0410-248
Bachmann-Gagescu R, Dempsey JC, Phelps IG, O’Roak BJ, Knutzen DM, Rue TC, Ishak GE, Isabella CR, Gorden N, Adkins J, Boyle EA, de Lacy N, O’Day D, Alswaid A, Ramadevi AR, Lingappa L, Lourenco C, Martorell L, Garcia-Cazorla A, Ozyurek H, Haliloglu G, Tuysuz B, Topcu M, Chance P, Parisi MA, Glass IA, Shendure J, Doherty D (2015) Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. J Med Genet 52:514–522. doi:10.1136/jmedgenet-2015-103087
Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG, Hall KP, Evers DJ, Barnes CL, Bignell HR, Boutell JM, Bryant J, Carter RJ, Keira Cheetham R, Cox AJ, Ellis DJ, Flatbush MR, Gormley NA, Humphray SJ, Irving LJ, Karbelashvili MS, Kirk SM, Li H, Liu X, Maisinger KS, Murray LJ, Obradovic B, Ost T, Parkinson ML, Pratt MR, Rasolonjatovo IM, Reed MT, Rigatti R, Rodighiero C, Ross MT, Sabot A, Sankar SV, Scally A, Schroth GP, Smith ME, Smith VP, Spiridou A, Torrance PE, Tzonev SS, Vermaas EH, Walter K, Wu X, Zhang L, Alam MD, Anastasi C, Aniebo IC, Bailey DM, Bancarz IR, Banerjee S, Barbour SG, Baybayan PA, Benoit VA, Benson KF, Bevis C, Black PJ, Boodhun A, Brennan JS, Bridgham JA, Brown RC, Brown AA, Buermann DH, Bundu AA, Burrows JC, Carter NP, Castillo N, Chiara ECM, Chang S, Neil Cooley R, Crake NR, Dada OO, Diakoumakos KD, Dominguez-Fernandez B, Earnshaw DJ, Egbujor UC, Elmore DW, Etchin SS, Ewan MR, Fedurco M, Fraser LJ, Fuentes Fajardo KV, Scott Furey W, George D, Gietzen KJ, Goddard CP, Golda GS, Granieri PA, Green DE, Gustafson DL, Hansen NF, Harnish K, Haudenschild CD, Heyer NI, Hims MM, Ho JT, Horgan AM et al (2008) Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456:53–59. doi:10.1038/nature07517
Bhogaraju S, Cajanek L, Fort C, Blisnick T, Weber K, Taschner M, Mizuno N, Lamla S, Bastin P, Nigg EA, Lorentzen E (2013) Molecular basis of tubulin transport within the cilium by IFT74 and IFT81. Science 341:1009–1012. doi:10.1126/science.1240985
Biesecker LG, Mullikin JC, Facio FM, Turner C, Cherukuri PF, Blakesley RW, Bouffard GG, Chines PS, Cruz P, Hansen NF, Teer JK, Maskeri B, Young AC, Program NCS, Manolio TA, Wilson AF, Finkel T, Hwang P, Arai A, Remaley AT, Sachdev V, Shamburek R, Cannon RO, Green ED (2009) The ClinSeq Project: piloting large-scale genome sequencing for research in genomic medicine. Genome Res 19:1665–1674. doi:10.1101/gr.092841.109
Chevrier V, Bruel AL, van Dam TJ, Franco B, Scalzo ML, Lembo F, Audebert S, Baudelet E, Isnardon D, Bole A, Borg JP, Kuentz P, Thevenon J, Burglen L, Faivre L, Riviere JB, Huynen MA, Birnbaum D, Rosnet O, Thauvin-Robinet C (2015) OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with Oral-Facial-Digital Syndrome. Hum Mol Genet. doi:10.1093/hmg/ddv488
Czarnecki PG, Shah JV (2012) The ciliary transition zone: from morphology and molecules to medicine. Trends Cell Biol 22:201–210. doi:10.1016/j.tcb.2012.02.001
Firat-Karalar EN, Rauniyar N, Yates JR 3rd, Stearns T (2014) Proximity interactions among centrosome components identify regulators of centriole duplication. Curr Biol 24:664–670. doi:10.1016/j.cub.2014.01.067
Gunay-Aygun M (2009) Liver and kidney disease in ciliopathies. Am J Med Genet C Semin Med Genet 151C:296–306. doi:10.1002/ajmg.c.30225
Jakobsen L, Vanselow K, Skogs M, Toyoda Y, Lundberg E, Poser I, Falkenby LG, Bennetzen M, Westendorf J, Nigg EA, Uhlen M, Hyman AA, Andersen JS (2011) Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods. EMBO J 30:1520–1535. doi:10.1038/emboj.2011.63
Kodani A, Yu TW, Johnson JR, Jayaraman D, Johnson TL, Al-Gazali L, Sztriha L, Partlow JN, Kim H, Krup AL, Dammermann A, Krogan NJ, Walsh CA, Reiter JF (2015) Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication. Elife. doi:10.7554/eLife07519
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291. doi:10.1038/nature19057
Lucas-Herald AK, Kinning E, Iida A, Wang Z, Miyake N, Ikegawa S, McNeilly J, Ahmed SF (2015) A case of functional growth hormone deficiency and early growth retardation in a child with IFT172 mutations. J Clin Endocrinol Metab 100:1221–1224. doi:10.1210/jc.2014-3852
Ng PC, Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Res 11:863–874. doi:10.1101/gr.176601
Parisi MA (2009) Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C Semin Med Genet 151C:326–340. doi:10.1002/ajmg.c.30229
Parisi M, Glass I (1993) Joubert syndrome and related disorders. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews®, University of Washington, Seattle, WA
Pedersen LB, Christensen ST (2012) Regulating intraflagellar transport. Nat Cell Biol 14:904–906. doi:10.1038/ncb2569
Pedersen LB, Rosenbaum JL (2008) Intraflagellar transport (Ift): role in ciliary assembly, resorption and signalling. Ciliary Funct Mamm Dev 85:23–61. doi:10.1016/S0070-2153(08)00802-8
Romani M, Micalizzi A, Valente EM (2013) Joubert syndrome: congenital cerebellar ataxia with the molar tooth. Lancet Neurol 12:894–905. doi:10.1016/S1474-4422(13)70136-4
Sanders AA, de Vrieze E, Alazami AM, Alzahrani F, Malarkey EB, Sorusch N, Tebbe L, Kuhns S, van Dam TJ, Alhashem A, Tabarki B, Lu Q, Lambacher NJ, Kennedy JE, Bowie RV, Hetterschijt L, van Beersum S, van Reeuwijk J, Boldt K, Kremer H, Kesterson RA, Monies D, Abouelhoda M, Roepman R, Huynen MH, Ueffing M, Russell RB, Wolfrum U, Yoder BK, van Wijk E, Alkuraya FS, Blacque OE (2015) KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome. Genome Biol 16:293. doi:10.1186/s13059-015-0858-z
Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11:361–362. doi:10.1038/nmeth.2890
Shen M, Cai Y, Yang Y, Yan X, Liu X, Zhou T (2013) Centrosomal protein FOR20 is essential for S-phase progression by recruiting Plk1 to centrosomes. Cell Res 23:1284–1295. doi:10.1038/cr.2013.127
Teer JK, Mullikin JC (2010) Exome sequencing: the sweet spot before whole genomes. Hum Mol Genet 19:R145–R151. doi:10.1093/hmg/ddq333
Teer JK, Green ED, Mullikin JC, Biesecker LG (2012) VarSifter: visualizing and analyzing exome-scale sequence variation data on a desktop computer. Bioinformatics 28:599–600. doi:10.1093/bioinformatics/btr711
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Ponten F (2015) Proteomics. Tissue-based map of the human proteome. Science 347:1260419. doi:10.1126/science.1260419
Wei Q, Zhang YX, Li YJ, Zhang Q, Ling K, Hu JH (2012) The BBSome controls IFT assembly and turnaround in cilia. Nat Cell Biol 14:950. doi:10.1038/ncb2560
Zhang W, Kim PJ, Chen Z, Lokman H, Qiu L, Zhang K, Rozen SG, Tan EK, Je HS, Zeng L (2016) MiRNA-128 regulates the proliferation and neurogenesis of neural precursors by targeting PCM1 in the developing cortex. Elife. doi:10.7554/eLife11324
Acknowledgements
The authors thank the Joubert Syndrome and Related Disorders Foundation for their extensive support and the patients and their families who generously participated in this investigation. This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Author information
Authors and Affiliations
Consortia
Corresponding authors
Ethics declarations
Conflict of interest
All authors declare no conflict of interest.
Funding
This work was supported by the Intramural Research Program at the National Human Genome Research Institute, National Institutes of Health.
Rights and permissions
About this article
Cite this article
Stephen, J., Vilboux, T., Mian, L. et al. Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency. Hum Genet 136, 399–408 (2017). https://doi.org/10.1007/s00439-017-1765-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-017-1765-z