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, BCOR4) in affected males from the family with Lenz syndrome previously used to identify the MAA2 locus. 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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The authors thank the families with Lenz microphthalmia and OFCD who generously volunteered to participate in this research project; T. Wolfsberg for bioinformatics assistance with identifying EST AI354165; R. Kittles for control DNA specimens; L. Samuels for assistance with contacting one affected individual; E. Tsilou and B. Rubin for ophthalmologic assessment of an individual with OFCD; J. Johnston for analyzing a set of controls for the nt254C→T mutation; and D. Zarkower for critical reading of the manuscript. This work was supported by funding from the Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health (L.G.B.) and an NIH extramural grant (V.J.B.). G.C.M.B., a Senior Research Fellow in Clinical Science, and R.P. are funded by the Wellcome Trust.