Abstract
Niemann-Pick type C disease is a lysosomal storage disease affecting primarily the nervous system that results in premature death. Here we present the first report and investigation of Niemann-Pick type C disease in Australian Angus/Angus-cross calves. After a preliminary diagnosis of Niemann-Pick type C, samples from two affected calves and two obligate carriers were analysed using single nucleotide polymorphism genotyping and homozygosity mapping, and NPC1 was considered as a positional candidate gene. A likely causal missense variant on chromosome 24 in the NPC1 gene (NM_174758.2:c.2969C>G) was identified by Sanger sequencing of cDNA. SIFT analysis, protein alignment and protein modelling predicted the variant to be deleterious to protein function. Segregation of the variant with disease was confirmed in two additional affected calves and two obligate carrier dams. Genotyping of 403 animals from the original herd identified an estimated allele frequency of 3.5%. The Niemann-Pick type C phenotype was additionally confirmed via biochemical analysis of Lysotracker Green, cholesterol, sphingosine and glycosphingolipids in fibroblast cell cultures originating from two affected calves. The identification of a novel missense variant for Niemann-Pick type C disease in Angus/Angus-cross cattle will enable improved breeding and management of this disease in at-risk populations. The results from this study offer a unique opportunity to further the knowledge of human Niemann-Pick type C disease through the potential availability of a bovine model of disease.
Highlights
Based on the suspicion of an inherited neurodegenerative disease, calf 1 was genotyped for two mutations known to cause bovine α-mannosidosis, a lysosomal storage disease that has been previously described in Angus and Galloway cattle (OMIA 000625–9913) [36, 37, 59]
A lysosomal storage disease (LSD), α-mannosidosis, which was first reported in Australian Angus cattle in 1957 [61] was considered
Cattle diagnosed with α-mannosidosis display head tremors, ataxia, incoordination and failure to thrive, leading to premature death [61]
Summary
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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