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

David Ng, Nalin Thakker, Connie M. Corcoran, Dian Donnai, Rahat Perveen, Adele Schneider, Donald W. Hadley, Cynthia Tifft, Liqun Zhang, Andrew O M Wilkie, Jasper J. Van Der Smagt, Robert J. Gorlin, Shawn M. Burgess, Vivian J. Bardwell, Graeme C M Black, Leslie G. Biesecker

    Research output: Contribution to journalArticlepeer-review


    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.
    Original languageEnglish
    Pages (from-to)411-416
    Number of pages5
    JournalNature Genetics
    Issue number4
    Publication statusPublished - Apr 2004


    • genetics: Abnormalities, Multiple
    • Amino Acid Sequence
    • Animals
    • Dosage Compensation (Genetics)
    • genetics: Eye Abnormalities
    • abnormalities: Face
    • genetics: Heart Defects, Congenital
    • Humans
    • Molecular Sequence Data
    • Mutation
    • chemistry: Proto-Oncogene Proteins
    • chemistry: Repressor Proteins
    • Research Support, Non-U.S. Gov't
    • Research Support, U.S. Gov't, P.H.S.
    • Sequence Homology, Amino Acid
    • Syndrome
    • genetics: Tooth Abnormalities
    • X Chromosome
    • Zebrafish


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