Here we present an infant boy carrying a missense mutation (p. R540Q) in BCOR. Deletion, truncation and frame-shift mutations in BCOR could result in severe phenotypic consequences and are lethal in male. To date, only two male patients have been identified to have a same missense mutation (p.P85L) mutation in BCOR ( Ng et al., 2004uanduHilton et al., 2009). Together with our finding, these results
suggest that amino GF 109203X
substitutions may have a less deleterious result compared with other variants that resulted in premature termination codons (PTCs).
Lenz microphthalmia syndrome (LMS) and oculo-facio-cardio-dental syndrome are both X-linked syndromes of microphthalmia, and these two syndromes should be considered allelic. It has been suggested that hemizygous males who carry a missense mutation in BCOR have Lenz microphthalmia syndrome while heterozygous females carrying a null allele have OFCD syndrome ( Hilton et al., 2009). Eye problems of Lenz microphthalmia syndrome may include coloboma, microcornea, and glaucoma. In our study, the patient had congenital glaucoma, which is a higher risk for eye disease. Our patient also had CHD and cerebral white matter hypoplasia. However, dental problems and intellectual disability could not be determined due to the patient\'s young age. For these reasons, we cannot determine the exact clinical diagnosis of this patient.
AxenfeldaRiegersyndrome (ARS) is an autosomal dominant disease characterized by malformations of the eyes and dental anomalies which are mainly linked to mutations in PITX2 ( Chang et al., 2012). ARS has several overlapping phenotypes, i.e. ocular and dental abnormalities with Lenz microphthalmia/OFCD, suggesting that these two syndromes share a similar underlying mechanism ( Li et al., 2014uanduTanaka et al., 2014). PITX2 has long been considered as an upstream regulator of the leftaright (LR) transcriptional hierarchy and plays a crucial role in the patterning of LR asymmetry in early embryonic development. In fact, mutations in PITX2 can cause lateral specification defects in humans ( Lin et al., 1999uanduPerveen et al., 2000). Subsequent studies with Xenopus demonstrated that dysfunction of BCOR suppresses the expression
of Pitx2 in the left lateral plate mesoderm (LPM) ( Hilton et al., 2007). A recent study shows that dysfunction of the BCL6/BCOR complex can cause uncontrolled Notch signaling, leading to the suppression of Pitx2 gene in the left LPM ( Tanaka et al., 2014). Consistent with theses notes, our patient has complex CHD, dextrocardia. Further studies will be necessary to dissect the molecular pathogenesis of Lenz microphthalmia/OFCD syndrome in detail.
BCOR was originally identified as a corepressor of BCL6 ( Huynh et al., 2000). Through its different motifs, BCOR interacts with several proteins, i.e. BCL6, AF9 and NSPC1. Histone deacetylases (HDACs) class I and II have also been shown to interact with BCOR, suggesting a possible link between the BCOR and epigenetic mechanisms ( Fan et al., 2009). Recently, the minimal BCL6 binding site was revealed within residues 498a514 (Ghetu et al., 2008). The mutation site in our study (p.R540Q) is located downstream of the BCL6 binding site. We suspect that this mutation might have a deleterious effect on the interaction between BCOR and other proteins rather than the interaction between BCOR and BCL6. In addition, it was reported that a truncated BCOR protein (deletion with the BCL6 binding domain) showed equivalent repression effect as that of wild type BCOR (Ng et al., 2004). Therefore further studies are warranted to understand the role of BCOR in eye and cardiac development.