Molecular genetics of cone-rod dystrophy : loss of ADAM9 leads to cone-rod dystrophy; mutations in CNNM4 cause Jalili syndrome, consisting of cone-rod dystrophy and amelogenesis imperfecta

• Main Author: Parry, David Alasdair
• Published: University of Leeds 2011
• Subjects: 617.7
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555849

The term "cone-rod dystrophy" (CORD) describes a clinically heterogeneous group of progressive retinal dystrophies characterised by predominant or equal loss of cone compared to rod photoreceptors, reduced ' visual acuity, colour vision abnormalities, photophobia and visual field loss. Over 20 genes and loci have been associated with CORD to date. This thesis details the discovery of mutations in two genes not previously known to be associated with CORD or retinal function in families with CORD in isolation and families with Jalili syndrome. Refinement of the previously published CORD9 locus by microsatellite and SNP genotyping followed by screening of candidate genes identified mutations in the gene ADAM9 in the original CORD9 family and three further consanguineous families autozygous for the CORD9 region. Examination of A dam 9-1- mice identified a progressive retinal degeneration in these animals which appears to manifest first as a defect in the interface between photoreceptor outer segments and the retinal pigment epithelium. Jalili syndrome, consisting of recessively inherited CORD and amelogenesis imperfecta, was first described in a large consanguineous family from the Gaza strip and subsequently linked to a region on chromosome 2. Genotyping of six additional families with this condition confirmed the existence of a genetically homogenous .: condition and refined the candidate region to an 11 Mb interval. Sequencing of candidate genes uncovered biallelic mutations in CNNM4, a putative metal transporter in all families tested. Immunolocalisation .of the protein confirmed expression in the neural retina and ameloblasts of the developing tooth.