A feline model of human low-density lipoprotein receptor-related atherosclerosis

Abstract

Atherosclerosis, a chronic inflammatory vascular disease driven by the accumulation of low-density lipoprotein-derived cholesterol on arterial walls, is the leading cause of mortality in humans worldwide but is rare in animals. We recently identified spontaneous atherosclerosis in the Korat cat breed, characterized by severe hypercholesterolemia and clinical signs of congestive heart failure, ultimately leading to death. Histopathological examination revealed lesions similar to those observed in human atherosclerosis. Given the close genetic relationship among affected cats, we hypothesized a genetic basis for the condition. We employed whole genome sequencing of a trio (one case and its parents) to identify genetic variants associated with the condition. We identified a homozygous XM_003981898.6:c.2406G>A variant specific to the cases in the LDLR gene. This variant is predicted to result in a premature stop codon, XP_003981947.3:p.(Trp758*), leading to a truncated LDLR protein that lacks the last 108 amino acids, including the transmembrane and intracellular C-terminal domains. Genotyping this LDLR variant in a cohort of 309 Korat cats confirmed its segregation and revealed new homozygous cats for clinical follow-up. In silico analyses demonstrated that the identified variant appears optimal for gene-editing-based therapeutics. In conclusion, we have described cats with a truncating LDLR defect. Given that PCSK9, another known hypercholesterolemia gene, has been lost in cats during evolution, our study is likely to provide an exciting double knockout model for human atherosclerosis research and therapeutics.