A Complex Ocular Phenotype of Early–Onset Long Anterior Lens Zonules and Late–Onset Autosomal Dominant Age–Related Macular Degeneration Due to a CTRP5 Gene Mutation

Abstract

Abstract: : Purpose: We evaluated the genetics of a complex ocular phenotype that involves both anterior and posterior segments in family UM:H389. Affected members have unusual long anterior zonules, detectable by the 3^rd decade, and/or autosomal dominant age–related macular degeneration (ADARMD) presenting in the 5^th decade. Methods: DNA from 58 family members was used for linkage, mapping and mutation analysis. Ocular examination included retinal funduscopy and fluorescein angiography, ERG, gonioscopy, biomicroscopy and IOP measurement. Linkage mapping set v2.5MD10 was used for a whole genome scan. Linkage analysis of ADARMD and the anterior zonules was performed independently using the affecteds only model. Mutation analysis of genes in the interval was carried out by direct sequencing. Tissue mRNA expression of CTRP5 was studied by qRT–PCR. Cellular patterns of CTRP5 expression in ocular tissue were determined by in situ hybridization. Results: Thirteen younger and 6 older family members had long zonules. Ten older members had ADARMD, including the 6 with long zonules. Zonules were not evaluated in the remaining 4 with ADRAMD. Two older subjects with long zonules and ADARMD also had ocular hypertension or glaucoma. Both conditions mapped independently to 11q23, with maximum LOD scores of 3.0 for ADARMD and 5.0 for zonules, both with zero recombination. The CTRP5 gene lies in this interval, and we identified the same missense mutation in all affected members. The retinal pigment epithelium and the ciliary epithelium gave the highest level of CTRP5 mRNA expression by qRT–PCR. These data were confirmed by in situ hybridization. Both of these tissues of neuroectodermal origin are involved in the pathogenic changes in affected family members. Conclusions: A single genetic locus at 11q23 is implicated in two seemingly disparate conditions that apparently involve epithelia of the anterior and posterior segments of the eye. All individuals with either long anterior zonules and/or ADARMD carry the same mutation in the CTRP5 gene, and CTRP5 transcript showed expression in both epithelia implicated in this complex ocular trait. Transmission of the mutation is consistent with an autosomal dominant trait. Elucidating the complex ocular phenotype may provide insights into processes of the anatomical variation of long zonules and age–related macular degeneration.

Keywords: age–related macular degeneration • anterior segment • mutations