Biology subjects

Hundi, S.

Publications and source records attributed to Hundi, S..

3 recordsLinked to original sources

bioRxiv2024

A feline model of human LDLR-related atherosclerosis

BackgroundAtherosclerosis, a chronic inflammatory vascular disease driven by the accumulation of LDL-derived cholesterol on arterial walls, is the leading cause of mortality 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. MethodsWe expanded our sample recruitment and employed whole genome sequencing to identify genetic variants associated with the condition. ResultsWe 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 an additional cohort of 309 Korat cats confirmed its segregation and revealed new affected cats for clinical follow-up. In silico analyses demonstrated that the identified variant appears optimal for gene-editing-based therapeutics. ConclusionsThis is the first report of a spontaneous atherosclerosis animal model with an LDLR variant, the most common gene associated with familial hypercholesterolemia in humans. Given that PCSK9, another known hypercholesterolemia gene, has been lost in many mammalian genomes, including cats, our study provides an exciting double knockout model for human atherosclerosis. The affected Korats may also serve as a valuable model for DNA base editing therapeutics.

genetics↗

bioRxiv2024

Determinants of de novo mutations in extended pedigrees of 43 dog breeds

Intensive breeding of dogs has had dramatic effects on genetic variants underlying phenotypes. To investigate whether this also affected mutation rates, we deep-sequenced pedigrees from 43 different dog breeds representing 404 trios. We find that the mutation rate is remarkably stable across breeds and is predominantly influenced by variation in parental ages. The effect of paternal age per year on mutation rates is approximately 1.5 times greater in dogs than humans, suggesting that the elevated yearly mutation rate in dogs is only partially attributed to earlier reproduction. While there is no significant effect of breeds on the overall mutation rate, larger breeds accumulate proportionally more mutations earlier in development than small breeds. Interestingly, we find a 2.6 times greater mutation rate in CG Islands (CGIs) compared to the remaining genome in dogs, unlike humans, where there is no difference. Our estimated rate of mutation by recombination in dogs is more than 10 times larger than estimates in humans. We ascribe these to the fact that canids have lost PRDM9-directed recombination and draw away recombination from CGIs. In conclusion, our study sheds light on stability of mutation processes and disparities in mutation accumulation rates reflecting the influence of differences in growth patterns among breeds, and the impact of PRDM9 gene loss on the de novo mutations of canids.

evolutionary biology↗

bioRxiv2024

IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta

Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in the ITPR3 gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J). In addition to peripheral neuropathy, immunodeficiency and tooth abnormalities are occasionally present. Here, we report the identification of a homozygous nonsense variant in the ITPR3 gene in Lancashire Heeler dogs, presenting with a severe developmental enamel defect and reduced nerve conduction velocity. We studied the primary skin fibroblasts of the affected dogs and observed that the nonsense variant in ITPR3 led to a complete absence of full-length IP3R3 protein. Unexpectedly, the protein levels of IP3R1 and IP3R2 were also markedly decreased, suggesting co-regulation. Functional Ca2+ measurements revealed reduced IP3R-mediated Ca2+ flux upon stimulation of G-protein-coupled-receptors in the affected dog fibroblasts. We were able to rescue the IP3R1 and IP3R2 depletion by proteasome inhibition but not the IP3R3 loss, which was facilitated by nonsense-mediated mRNA decay. These findings highlight the first spontaneous mammalian phenotype caused by a nonsense variant in ITPR3, leading to the loss of IP3R3. The human and canine IP3R3 proteins are highly similar, and our study suggests that the tissue involvement resulting from the receptors dysfunction is also conserved. In summary, IP3R3 is critical for enamel formation and peripheral nerve maintenance. Author summaryWe investigated pet dogs, Lancashire Heelers, with impairments in tooth development and in the nerves that regulate limb muscles. Through genetic studies of the dog pedigree, we found that the phenotypes were caused by a recessively inherited mutation in the ITPR3 gene, which encodes one of three IP3 receptors (IP3R) isoforms (IP3R3 isoform) that are needed for intracellular Ca2+ signaling. Mutated IP3R3 has been recently linked to a human inherited neuropathy called Charcot-Marie-Tooth disease type 1J, which impairs peripheral nerve function and is accompanied by immunodeficiency and abnormal teeth in some individuals. We showed that in the skin cells of the affected dogs, the full-length IP3R3 protein was completely absent, and also the protein levels of the other two IP3R isoforms (IP3R1 and IP3R2) were severely lowered. This led to impaired agonist-induced Ca2+ release and signaling. Our results demonstrate the high conservation between human and canine IP3 receptors and their significance for different tissue systems. The genetic studies now highlight that IP3R3 is vital for peripheral nerve function and enamel development.

genetics↗