OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin.
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.
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands.
Karlien L M
KL
Coene
Ronald
R
Roepman
Dan
D
Doherty
Bushra
B
Afroze
Hester Y
HY
Kroes
Stef J F
SJ
Letteboer
Lock H
LH
Ngu
Bartlomiej
B
Budny
Erwin
E
van Wijk
Nicholas T
NT
Gorden
Malika
M
Azhimi
Christel
C
Thauvin-Robinet
Joris A
JA
Veltman
Mireille
M
Boink
Tjitske
T
Kleefstra
Frans P M
FP
Cremers
Hans
H
van Bokhoven
Arjan P M
AP
de Brouwer
D000818:Animals; D005136:Eye Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008126:Lod Score; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D013577:Syndrome; D020798:Two-Hybrid System Techniques; D014960:X Chromosome
D005136:Eye Proteins; C522405:LCA5 protein, human; C544473:LCA5 protein, rat; D008869:Microtubule-Associated Proteins; C115130:OFD1 protein, human; C544472:OFD1 protein, rat; D011506:Proteins