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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.
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页码:465 / 481
页数:17
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