RESUMO
PURPOSE: To identify the gene responsible for a complex ocular phenotype of late-onset macular degeneration, long anterior zonules (LAZ), and elevated intraocular pressure (IOP) and to study its expression. METHODS: Ocular examination, visual field, fluorescein angiography, and electrophysiology testing were performed. One affected individual was treated with vitamin A. DNA from 55 family members (UM:H389) was used for linkage, mapping, and mutation analysis. Linkage analysis of macular degeneration and LAZ phenotypes was performed independently. Mutations in candidate genes were screened by sequencing. mRNA expression of CTRP5 and MFRP, which are bicistronic genes, was studied by semiquantitative RT-PCR (qRT-PCR) in various human tissues. CTRP5 expression was also evaluated by in situ hybridization. RESULTS: Affected members had LAZ detectable by the third decade and/or macular degeneration by the fourth to fifth decade. A six-month treatment with vitamin A shortened dark adaptation considerably in one affected member. Both conditions mapped independently with zero recombination to 11q23, with maximum lod scores of 3.31 for macular degeneration and 5.41 for LAZ. The same CTRP5 missense mutation was identified in all affected individuals. Retinal pigment epithelium (RPE) and ciliary epithelium (CE) showed highest CTRP5 transcript expression, which was also true for MFRP. CTRP5 tissue expression was confirmed by in situ hybridization. CONCLUSIONS: A single locus at 11q23 is implicated in a complex ocular phenotype involving RPE and CE, tissues of neuroectodermal origin. All individuals with either LAZ and/or macular degeneration carry the same CTRP5 S163R mutation, which is transmitted in autosomal dominant manner.