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

• Published in: American journal of human genetics Vol. 85; no. 4; pp. 465 - 481
• Main Authors: Coene, Karlien L.M., Roepman, Ronald, Doherty, Dan, Afroze, Bushra, Kroes, Hester Y., Letteboer, Stef J.F., Ngu, Lock H., Budny, Bartlomiej, van Wijk, Erwin, Gorden, Nicholas T., Azhimi, Malika, Thauvin-Robinet, Christel, Veltman, Joris A., Boink, Mireille, Kleefstra, Tjitske, Cremers, Frans P.M., van Bokhoven, Hans, de Brouwer, Arjan P.M.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 09.10.2009; Cell Press; Elsevier
• Subjects: Animals; Biological and medical sciences; Eye Proteins - genetics; Family Health; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic disorders; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Humans; Lod Score; Male; Medical genetics; Medical sciences; Metabolic diseases; Microtubule-Associated Proteins - genetics; Miscellaneous; Molecular and cellular biology; Mutation; NMR; Nuclear magnetic resonance; Other metabolic disorders; Proteins; Proteins - genetics; Rats; Rats, Wistar; Sex Factors; Syndrome; Two-Hybrid System Techniques; X Chromosome; Malaysia; Endocrinopathy; Human; Sex linked character; Nervous system diseases; Joubert syndrome; Metabolic diseases; Cardiovascular disease; Metabolic syndrome; Cerebral disorder; Genetic disease; Malformation; Central nervous system disease; Genetics; X-Chromosome
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2009.09.002

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.