A feline model of human LDLR-related atherosclerosis

Hytonen, M. K.; Karkamo, V.; Hundi, S.; Airas, N.; Kaukonen, M.; Sukura, A.; Lyons, L. A.; Anderson, H. A.; Kareinen, I.; Lohi, H.

doi:10.1101/2024.12.04.626782

bioRxiv · 10.1101/2024.12.04.626782

A feline model of human LDLR-related atherosclerosis

Hytonen, M. K.·Karkamo, V.·Hundi, S.·Airas, N.·Kaukonen, M.·Sukura, A.·Lyons, L. A.·Anderson, H. A.·Kareinen, I.·Lohi, H.

View original source ↗Export metadata ↓

Abstract

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.

Explore related subjects

genetics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Hytonen, M. K., Karkamo, V., Hundi, S., Airas, N., Kaukonen, M., Sukura, A., Lyons, L. A., Anderson, H. A., Kareinen, I., Lohi, H.. 2024-12-07. A feline model of human LDLR-related atherosclerosis. https://doi.org/10.1101/2024.12.04.626782

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Pangenome Discoveries from Clinical Long-Read Genomes in Underrepresented Populations with Neurodevelopmental Disorders

Genetic diagnoses remain elusive for many individuals with neurodevelopmental disorders (NDDs), and the gap is wider in populations poorly represented in genomic reference resources. To demonstrate the equitable advantage of long-read whole genome sequencing (LR-WGS) and pangenomes in terms of clinical utility, we analyzed 211 NDD cases and 107 unaffected relatives from 24 populations, integrating their assemblies, resulting in a total of 1204 haplotypes with the Human Pangenome Reference Consortium Release 2 (HPRC_r2) and the Arab Pangenome Reference (APR) datasets. Clinical interpretation of small variants and structural variants (SVs) revealed pathogenic or likely pathogenic findings in 38.9% of the cases (82/211), and our workflow further detected pathogenic repeat expansions in 3.8% of the cases and runs of homozygosity (ROHs) exceeding 300 Mb in 4.7% of the cases, revealing substantial autozygosity suggestive of strong inbreeding. Beyond these clinical assessments, pangenome analysis revealed 3.9 million population-level novel small variants, 39,782 SVs and an average of 2.17 Mb of novel sequence per individual absent from linear references and global pangenomes. We identified 85.9 kb of case-unique nonreference sequences in exonic segments overlapping with curated NDD gene sets. Graph-based tertiary analysis further identified rare exonic complex homozygous rearrangements in the NDD associated genes for 2.4% of the cases. Together, these findings emphasize how diverse genome assemblies extend variant discovery beyond established linear reference-based clinical interpretation.

genetics↗

bioRxiv2026

Integrated exome-transcriptome analysis of a schizophrenia case with an exceptionally low polygenic risk score

Schizophrenia liability reflects both common polygenic variation and rarer variants of larger effect. We investigated a post-mortem schizophrenia case (SZ07) with a schizophrenia polygenic risk score below the first percentile among ancestry-matched cases, asking whether individual-level genomic and transcriptomic analyses could help identify potentially novel schizophrenia-relevant variants. We used exome analysis with multiple variant-prediction tools to generate a panel of variants and corresponding candidate genes potentially implicated in the pathological process in SZ07. The prioritised variants were then assessed using RNA sequencing of three cortical regions. Of these, only an IZUMO4 splice-acceptor variant showed direct RNA-level support. Beyond variant-specific analyses, we characterised broader transcriptomic abnormalities in the SZ07 brain. Pathway analysis of gene-level expression deviations implicated innate immune processes, calcium signalling, synaptic biology, and axon remodelling. Notably, compared with conventional single-sample biological pathway analysis, the analysis we used showed only a weak association with neuronal specificity, suggesting their reduced sensitivity to the main axis of variation related to cellular composition in bulk brain tissue gene expression data. Although the candidate genes showed no significant pathway-level convergence, the broader transcriptomic profile revealed coherent biological alterations largely compatible with the documented history of cerebrovascular disease in SZ07. These results demonstrate how the integration of exome and transcriptome data at the individual level enables the formulation and constraint of hypotheses regarding patient-specific genetic features and their molecular consequences, while highlighting important limitations related to tissue composition, comorbidity, and the choice of reference cohort.

genetics↗

bioRxiv2026

A genetic screen to identify host factors required for commensal bacterial adherence to the gut epithelia

Bacterial adherence to gut epithelial cells likely involves host genetic components. We isolated a gut commensal bacterium, Lelliottia jeotgali, that can robustly colonize C. elegans through attachment to intestinal epithelial cells. Here, we developed a novel screen in C. elegans to identify host genes required for microbiome bacterial colonization. Using transgenic L. jeotgali strain expressing tdTomato, we conducted forward genetic screens in C. elegans to select for mutants that completely lost colonization. We identified multiple allelic mutations in five different C. elegans genes, termed knockout of Lelliottia adherence (kola) mutants, with a near complete loss of adherence. Each of kola-1-5 is uncharacterized and predicted to encode for a secreted or membrane-bound protein. We also identified gly-5, a GalNAc transferase that initiates O-linked glycosylation. Overall, we describe the first C. elegans screen to identify host factors that control microbiome bacterial colonization in the gut.

genetics↗