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

Abstract

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 OFCDmutant 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.We had previously localized MAA2 to a 10-Mb candidate region of Xp 3 . To identify the gene, we narrowed this region by excluding regions deleted in males with Xp deletions but without microphthalmia. Coriell cell line GM07947 is from a male with Duchenne muscular dystrophy, chronic granulomatous disease, McLeod phenotype and retinitis pigmentosa without microphthalmia 5 . Sequence-tagged site (STS) mapping confirmed previous data and oriented it to current genome maps. The deletion extended from DMD (telomeric) to between RPGR and OTC (centromeric; Fig. 1). The Coriell cell line GM10283 excluded two genes telomeric to DMD. This narrowed the critical region to ∼5 Mb, including 12 identified genes not known to be mutated in humans. One of these, DDX3, has an active Y homolog, and we therefore considered it unlikely to underlie a disorder with X-linked recessive inheritance. We sequenced the remaining 11 genes in members of the family in which MAA2 was originally identified. Ten of these genes showed no alterations, but we identified a missense change (nt 254C→T) in BCOR 4 that co-segregated with the disease phenotype (lod score of 2.46, above the threshold of 2.0 for X linkage 3 ). The corresponding residue of human BCOR, Pro85, is conserved in mouse, rat, chicken and pufferfish (Fig. 2), and we did not detect the nt 254C→T mutation among >450 control chromosomes. X-inactivation studies of peripheral blood leukocytes in two carriers of the mutation showed no ske...

Far from solved: A perspective on what we know about early mechanisms of left–right asymmetry

“…Like in frog (Hilton et al, 2007;Sakano et al, 2010), BCoR mutations randomize LR asymmetry in human embryos (Ng et al, 2004;Hilton et al, 2007), but this does not occur in mouse (Ye et al, 1997;Yoshida et al, 1999). The loss of brain asymmetry observed in mouse mutants with ciliary dyskinesia (Kawakami et al, 2008) is not observed in human patients (Kennedy et al, 1999;Tanaka et al, 1999;McManus et al, 2004;Afzelius and Stenram, 2006).…”

Characterization of Bcor expression in mouse development

“…In addition to its role in B-cells, BCOR aids in the control of gene expression in multiple tissues and organ systems during development and into adulthood as mutations in human BCOR result in X-linked Oculofaciocardiodental syndrome (OFCD) (Ng et al, 2004). OFCD is the primary subtype of OMIM #300166 microphthalmia, syndromic 2 (MCOPS2) and is characterized by ocular, dental, cardiac and digital anomalies in heterozygous females (Ng et al, 2004;Schulze et al, 1999).…”

“…OFCD is the primary subtype of OMIM #300166 microphthalmia, syndromic 2 (MCOPS2) and is characterized by ocular, dental, cardiac and digital anomalies in heterozygous females (Ng et al, 2004;Schulze et al, 1999). Males with OFCD do not survive due to presumed embryonic lethality (Ng et al, 2004).…”

“…OFCD is the primary subtype of OMIM #300166 microphthalmia, syndromic 2 (MCOPS2) and is characterized by ocular, dental, cardiac and digital anomalies in heterozygous females (Ng et al, 2004;Schulze et al, 1999). Males with OFCD do not survive due to presumed embryonic lethality (Ng et al, 2004). Since BCOR lies on the X chromosome in both mice and humans, random X-inactivation results in mosaic expression of the mutant allele contributing to varying disease severity in females (Ng et al, 2004;Schulze et al, 1999).…”

“…Males with OFCD do not survive due to presumed embryonic lethality (Ng et al, 2004). Since BCOR lies on the X chromosome in both mice and humans, random X-inactivation results in mosaic expression of the mutant allele contributing to varying disease severity in females (Ng et al, 2004;Schulze et al, 1999). Additionally, peripheral leukocytes of female patients show preferential survival of cells in which the mutant allele of BCOR lies on the inactivated X chromosome, indicating a strong requirement for BCOR in hematopoiesis (Hedera and Gorski, 2003;Ng et al, 2004).…”