OFD1 Is Mutated in X-Linked Joubert Syndrome and Interacts with LCA5-Encoded Lebercilin |
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Authors: | Karlien LM Coene Ronald Roepman Dan Doherty Hester Y Kroes Lock H Ngu Erwin van Wijk Malika Azhimi Joris A Veltman Mireille Boink Frans PM Cremers Hans van Bokhoven Arjan PM de Brouwer |
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Institution: | 1 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands 2 Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands 3 Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands 4 Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Hospital, Seattle, WA 98195, USA 5 Division of Clinical Genetics, Pediatrics Institute, Kuala Lumpur Hospital, Kuala Lumpur 50586, Malaysia 6 Department of Medical Genetics, University Medical Center Utrecht, Utrecht 3508 AB, The Netherlands 7 Department of Medical Genetics, Poznan University of Medical Sciences, Poznan 60-352, Poland 8 Centre de Génétique, Hôpital d'Enfants, Dijon 21079, France |
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Abstract: | We ascertained a multi-generation Malaysian family with Joubert syndrome (JS). The presence of asymptomatic obligate carrier females suggested an X-linked recessive inheritance pattern. Affected males presented with mental retardation accompanied by postaxial polydactyly and retinitis pigmentosa. Brain MRIs showed the presence of a “molar tooth sign,” which classifies this syndrome as classic JS with retinal involvement. Linkage analysis showed linkage to Xpter-Xp22.2 and a maximum LOD score of 2.06 for marker DXS8022. Mutation analysis revealed a frameshift mutation, p.K948NfsX8, in exon 21 of OFD1. In an isolated male with JS, a second frameshift mutation, p.E923KfsX3, in the same exon was identified. OFD1 has previously been associated with oral-facial-digital type 1 (OFD1) syndrome, a male-lethal X-linked dominant condition, and with X-linked recessive Simpson-Golabi-Behmel syndrome type 2 (SGBS2). In a yeast two-hybrid screen of a retinal cDNA library, we identified OFD1 as an interacting partner of the LCA5-encoded ciliary protein lebercilin. We show that X-linked recessive mutations in OFD1 reduce, but do not eliminate, the interaction with lebercilin, whereas X-linked dominant OFD1 mutations completely abolish binding to lebercilin. In addition, recessive mutations in OFD1 did not affect the pericentriolar localization of the recombinant protein in hTERT-RPE1 cells, whereas this localization was lost for dominant mutations. These findings offer a molecular explanation for the phenotypic spectrum observed for OFD1 mutations; this spectrum now includes OFD1 syndrome, SGBS2, and JS. |
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