Identification of causative mutations in Abyssinian Amyloidosis

Amyloidosis is a metabolic disorder caused by the improper folding of autologous proteins that aggregate and deposit into different organs. This disease occurs in humans, chickens, wild and domestic felids and several other species. Familial forms were noticed in Abyssinian/Somali and Siamese/Oriental cat breeds, with liver and kidney, respectively, as main targets for the deposits. The amyloidosis pathogenic pathway is still unknown and no DNA test is available for a preventive diagnosis. The aim of this study is to identify the causative mutations of the disease in the Abyssinian cats, using different genetic and genomic approaches. Whole genome sequences of two affected Abyssinians were used to identify mutations associated with amyloidosis, using 127 additional whole genome cat sequences from unaffected cats as controls for variant exclusion. Identified variants were prioritized based on a previous genome wide association study conducted on affected/healthy cohorts of Abyssinians. Significant associations on cat chromosomes B4 and C2 were detected. Among all the genes within the two regions, two were considered good candidates for their potential role in the pathogenic pathway of the disease and showed polymorphisms only within affected individuals. Twenty-eight additional variants were found on different chromosomes and to confirm the causality link to the disorder, the polymorphisms were genotyped on a large population of affected and control Abyssinians, including 20 related cats. Currently the genotype-phenotype association is under evaluation considering different possible modes of inheritance, including a polygenic contribution to the disease.