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

被引:157
作者
Coene, Karlien L. M. [1 ,2 ]
Roepman, Ronald [1 ,2 ]
Doherty, Dan [4 ,5 ]
Afroze, Bushra [6 ]
Kroes, Hester Y. [7 ]
Letteboer, Stef J. F. [1 ]
Ngu, Lock H. [6 ]
Budny, Bartlomiej [8 ]
van Wijk, Erwin [3 ]
Gorden, Nicholas T. [4 ,5 ]
Azhimi, Malika [1 ]
Thauvin-Robinet, Christel [9 ]
Veltman, Joris A. [1 ,2 ]
Boink, Mireille [1 ]
Kleefstra, Tjitske [1 ]
Cremers, Frans P. M. [1 ,2 ]
van Bokhoven, Hans [1 ,2 ]
de Brouwer, Arjan P. M. [1 ,2 ]
机构
[1] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands
[2] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, NL-6500 HB Nijmegen, Netherlands
[3] Radboud Univ Nijmegen, Med Ctr, Dept Otorhinolaryngol, NL-6500 HB Nijmegen, Netherlands
[4] Univ Washington, Dept Pediat, Sch Med, Seattle, WA 98195 USA
[5] Seattle Childrens Hosp, Seattle, WA 98195 USA
[6] Kuala Lumpur Hosp, Inst Pediat, Div Clin Genet, Kuala Lumpur 50586, Malaysia
[7] Univ Med Ctr Utrecht, Dept Med Genet, NL-3508 AB Utrecht, Netherlands
[8] Poznan Univ Med Sci, Dept Med Genet, PL-60352 Poznan, Poland
[9] Hop Enfants, Ctr Genet, F-21079 Dijon, France
基金
美国国家卫生研究院;
关键词
BASAL BODY PROTEIN; DIGITAL SYNDROME TYPE-1; PRIMARY CILIA FORMATION; GENE-EXPRESSION; RENAL SYNDROME; SENIOR-LOKEN; MUTATIONS; CEP290; DNA; NEPHRONOPHTHISIS;
D O I
10.1016/j.ajhg.2009.09.002
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
We ascertained a multi-generation Malaysian family with Joubert syndrome US). 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.
引用
收藏
页码:465 / 481
页数:17
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