Characterization of the Human Gene Encoding MT-protocadherin, a Candidate Gene for Autosomal Recessive Retinitis Pigmentosa

Abstract

Abstract: : Purpose: The gene for MT-protocadherin (MT-PCDH) is specifically expressed in the photoreceptor cells. It has been shown that photoreceptors of Mt-Pcdh knockout mice develop disorganized and fragmented outer segments and degenerate. Thus MT-PCDH is an excellent candidate for human retinal degeneration. Methods: We performed mutation screening by SSCP in 224 patients with sporadic or autosomal recessive retinitis pigmentosa. Samples showing altered electrophoretic mobility were sequenced. Results: Human MT-PCDH consists of 17 exons (ranging in size from 51 to 540 bp). A highly polymorphic CA repeat was identified in intron 9. Two of the patients carried heterozygous missense changes, A212T in exon 7, and P532A in exon 15. Both mutations affect residues that are evolutionarily conserved in the rat orthologue and the putative Drosophila orthologue CG6445. No alteration on the second allele was identified in either patient. Neither of the changes were detected in 100 control DNAs. Only one other missense change, N623S, was detected in a third patient and several unaffected individuals, indicating that the coding region of MT-PCDH exhibits little variability. However, 14 non-coding sequence variants were identified in patients that were also present in unaffected individuals. Conclusions: Cadherins are Ca²⁺-binding, transmembrane proteins involved in cell adhesion. In human, more than 80 different cadherins have been characterized to date. The identification of mutations in three cadherin genes in patients with various sensory disorders, many of them with photoreceptor degeneration as a major feature (cadherin-23/CDH23 for Usher syndrome type 1D (USH1D), protocadherin-15 for USH1F, and cadherin-3 for macular dystrophy with hypotrichosis), revealed the importance of cadherins for retinal integrity. It is possible that A212T and P532A are disease causing implying that, in each case, the second mutation escaped detection. Although we could not prove a causative role of MT-PCDH mutations in retinal degeneration, retina-specific expression of the gene, its close phylogenetic relationship to CDH23, and the retinal dystrophy phenotype of Mt-Pcdh knockout mice make this gene an interesting candidate for recessive RP and/or other retinal dystrophies.

Keywords: candidate gene analysis • retinitis • cell adhesions/cell junctions