A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy

摘要: The bovine form of the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) shows striking similarity to human disease. It has, however, been mapped a genomic region not harboring orthologue SMN gene, mutation which causes SMA. After refinement mapping results we analyzed positional and functional candidate genes. One three genes, FVT1, encoding 3-ketodihydrosphingosine reductase, catalyzes crucial step in glycosphingolipid metabolism, showed G-to-A missense that changes Ala-175 Thr. identified is limited SMA-affected animals carriers always appears context founder haplotype. Ala variant found healthy expected reductase activity an vitro enzyme assay. Importantly, Thr SMA no detectable activity. Surprisingly, vivo assay mutated gene complements growth defect homologous yeast knockout strain as well variant. This finding explains viability affected newborn calves later neuron-specific onset disease, might be due high sensitivity these neurons housekeeping functions. Taken together, described FVT1 strong for causality cattle. result provides animal model understanding underlying mechanisms development will allow efficient selection against