Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR

被引:251
作者
Ng, D
Thakker, N
Corcoran, CM
Donnai, D
Perveen, R
Schneider, A
Hadley, DW
Tifft, C
Zhang, LQ
Wilkie, AOM
van der Smagt, JJ
Gorlin, RJ
Burgess, SM
Bardwell, VJ
Black, GCM [1 ]
Biesecker, LG
机构
[1] St Marys Hosp, Acad Unit Med Genet, Manchester M13 0JH, Lancs, England
[2] St Marys Hosp, Reg Genet Serv, Manchester M13 0JH, Lancs, England
[3] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA
[4] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN USA
[5] Univ Minnesota, Ctr Canc, Minneapolis, MN USA
[6] Albert Einstein Med Ctr, Dept Genet, Philadelphia, PA 19141 USA
[7] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA
[8] NIDDKD, Genet Dev & Dis Res Branch, NIH, Bethesda, MD 20892 USA
[9] Childrens Natl Med Ctr, Div Genet, Washington, DC 20010 USA
[10] John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DS, England
[11] Univ Utrecht, Med Ctr, Dept Med Genet, NL-3508 AB Utrecht, Netherlands
[12] Univ Minnesota, Dept Oral Pathol & Genet, Sch Dent, Minneapolis, MN USA
[13] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA
[14] Ctr Mol Med, Manchester, Lancs, England
[15] Cent Manchester & Manchester Childrens Univ Hosp, Manchester Royal Eye Hosp, Manchester, Lancs, England
关键词
D O I
10.1038/ng1321
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Lenz microphthalmia is inherited in an X-linked recessive pattern and comprises microphthalmia, mental retardation, and skeletal and other anomalies. Two loci associated with this syndrome, MAA ( microphthalmia with associated anomalies) and MAA2, are situated respectively at Xq27-q28 (refs. 1,2) and Xp11.4-p21.2 (ref. 3). We identified a substitution, nt 254C --> T; P85L, in BCOR (encoding BCL-6-interacting corepressor, BCOR 4) in affected males from the family with Lenz syndrome previously used to identify the MAA2 locus 3. Oculofaciocardiodental syndrome (OFCD; OMIM 300166) is inherited in an X-linked dominant pattern with presumed male lethality and comprises microphthalmia, congenital cataracts, radiculomegaly, and cardiac and digital abnormalities. Given their phenotypic overlap, we proposed that OFCD and MAA2 - associated Lenz microphthalmia were allelic, and we found different frameshift, deletion and nonsense mutations in BCOR in seven families affected with OFCD. Like wild-type BCOR, BCOR P85L and an OFCD-mutant form of BCOR can interact with BCL-6 and efficiently repress transcription. This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6. We cloned the zebrafish (Danio rerio) ortholog of BCOR and found that knock-down of this ortholog caused developmental perturbations of the eye, skeleton and central nervous system consistent with the human syndromes, confirming that BCOR is a key transcriptional regulator during early embryogenesis.
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页码:411 / 416
页数:6
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