OFD1 Is Mutated in X-Linked Joubert Syndrome and Interacts with LCA5-Encoded Lebercilin

Karlien L.M. Coene, Ronald Roepman, Dan Doherty, Bushra Afroze, Hester Y. Kroes, Stef J.F. Letteboer, Lock H. Ngu, Bartlomiej Budny, Erwin van Wijk, Nicholas T. Gorden, Malika Azhimi, Christel Thauvin-Robinet, Joris A. Veltman, Mireille Boink, Tjitske Kleefstra, Frans P.M. Cremers, Hans van Bokhoven, Arjan P.M. de Brouwer

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169 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)465-481
Number of pages17
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 9 Oct 2009
Externally publishedYes


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