Molecular characterization of a familial translocation implicates disruption of HDAC9 and possible position effect on TGFbeta2 in the pathogenesis of Peters' anomaly.

Peters' anomaly (PA) is a congenital defect of the anterior chamber of the eye. We identified a family in which an apparently balanced chromosomal translocation t(1;7) (q41;p21) was associated with PA. Based on this observation, detailed molecular characterizations of the breakpoint regions and candidate genes were carried out. A candidate gene from each breakpoint was identified: on chromosome 7, histone deacetylase 9 (HDAC9), disrupted by the translocation breakpoint, and on chromosome 1, transforming growth factor-beta2 (TGFbeta2) located 500 kb proximal to the breakpoint. An additional lysophospholipase-like 1 gene (LYPLAL1), localized approximately 200 kb distal to the chromosome 1 breakpoint, was also identified and characterized. Although only the HDAC9 gene is disrupted by the breakpoint, we consider that TGFbeta2 represents the main candidate gene in this family, which is elicited in mice by the Tgfbeta2-null status and by the TGFbeta2-induced cataractus changes in animal models. As an alternative scenario, which is supported by the ability of class II HDACs to mediate extracellular TGF-beta stimuli to core histone deacetylation in promoter-adjacent regions, we propose the hypothesis of digenic inheritance. Inappropriate or inadequate TGFbeta2 expression, together with deficient mediation of these signals at the transcription level, due to an altered HDAC9 isoforms ratio, may also lead to the observed ocular phenotype.