Biology subjects

Abitbol, M.

Publications and source records attributed to Abitbol, M..

5 recordsLinked to original sources

bioRxiv2026

Missense LMNA Variant Compromises Nuclear Integrity and Sarcomeric Remodeling in Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation, and pathogenic variants in LMNA are a well-established cause of inherited DCM. The LMNA gene encodes nuclear lamins A/C, which maintain nuclear integrity, regulate gene expression and mediate mechanotransduction. Here, we investigated the pathogenic consequences of the NM_170707.4(LMNA):c.274C>T NP_733821.1:p.(Leu92Phe) variant, previously associated with lipodystrophy features, using patient-derived induced pluripotent stem cells, differentiated into cardiomyocytes and show implication of LMNA in sarcomere remodeling and mitochondria efficiency. We generated iPSC lines from two DCM patients carrying LMNA p.Leu92Phe variant in heterozygous form and a healthy parental control. Cardiomyocytes differentiation efficiency was preserved, however, LMNAp.Leu92Phe iPSC-CMs exhibited laminopathies associated phenotypes, such as nuclear shape abnormalities and lamin A/C aggregation. Moreover, in vitro study revealed that LMNA p.Leu92Phe iPSC-CMs alter sarcomere reformation and decrease mitochondrial respiration after cardiomyocyte remodeling, which is associated with a worsening nuclear shape phenotype. Functional analyses highlight defects in calcium handling, thereby explaining arrhythmia and dilated cardiomyopathy features in patients. Our results show that the LMNA p.Leu92Phe variant compromises nuclear lamina integrity and disrupts functional cardiomyocyte properties, particularly during sarcomere remodeling, highlighting the long-term impact of this specific variant in LMNA-associated DCM.

genetics↗

bioRxiv2025

Reproducibility of the evaluation of genetic variant pathogenicity based on the animal variant classification guidelines

Until recently, due to the absence of standardized guidelines tailored for veterinary use, the evaluation of genetic variant pathogenicity for single-gene diseases was based on a personal interpretation of the presented evidence, which has led to ambiguous interpretation. With the publication of the animal variant classification guidelines (AVCG), a more objective approach became available. Variants are evaluated based on twenty-three criteria and labeled as pathogenic, likely pathogenic, variant of uncertain significance, likely benign or benign. While the accuracy was thoroughly tested in the original publication, the reproducibility of the various steps involved was only briefly checked, which is why the current study was performed. Each variant from a set of 150 published likely causal variants for single-gene diseases from three species (dog, cat, horse) was independently and blindly assessed by three different reviewers, each applying the same AVCG. An overall agreement of 93% for decisions on the scope, i.e. whether they fit the inclusion criteria to allow evaluation with AVCG, was found. More importantly, the reproducibility was 65% for the pathogenicity classification and this increased to 83% clinically relevant agreement. While a direct comparison of the reproducibility with human literature is not possible for the scope, the reproducibility on pathogenicity classification is in line with reports using the human American College for Medical Genetics and Genomics and Association for Molecular Pathology guidelines for human variants. Overall, based on the current study, the reproducibility of the guidelines in veterinary species is within current expectations.

genetics↗

bioRxiv2025

A missense variant in PAOX in American Staffordshire Terriers with juvenile-onset polyneuropathy

Hereditary polyneuropathies in dogs mirror many features of human Charcot-Marie-Tooth (CMT) disease and offer valuable spontaneous models for discovery of genes variants involved in this disorder. A juvenile-onset polyneuropathy (JOP) in American Staffordshire Terriers (ASTs) resembles CMT, with motor and sensory deficits, often accompanied by laryngeal paralysis. To identify the underlying genetic cause, we conducted a genome-wide association study (GWAS) with 24 affected and 53 control ASTs that identified a significant locus at the distal end of chromosome 28. Homozygosity mapping analysis further defined a critical interval spanning 11 protein-coding genes and whole-genome sequencing revealed a missense variant in the PAOX gene encoding polyamine oxidase (NC_049249.1:g.41474541G>A), leading to a glycine-to-arginine substitution at a highly conserved residue, XP_038435135.1:p.(Gly382Arg). Genotypes at this variant were homozygous alternate in 96% of the affected dogs (n=53) and either homozygous reference or heterozygous in 336 unaffected ASTs; the mutant allele was not detected in any of 2519 genomes of other dog breeds. In silico predictions consistently supported its pathogenicity, and structural modeling suggested altered substrate binding. Although PAOX expression was preserved, proteomic profiling in affected nerve tissue revealed reduced levels of myelin-associated proteins, as well as dysregulation of mitochondrial and proteasomal pathways. Our findings establish this PAOX missense variant as the likely cause of JOP in ASTs and highlight the breed as a valuable large-animal model for studying inherited peripheral neuropathies. These results expand the spectrum of genes implicated in polyneuropathies and provide a basis for genetic testing and informed breeding strategies in ASTs. Author summaryWe studied a hereditary peripheral nerve disorder in American Staffordshire Terriers characterized by exercise intolerance, coordination problems, general weakness and difficulty breathing due to laryngeal paralysis. These signs closely resemble a group of inherited diseases in people known as Charcot-Marie-Tooth disease. To understand the genetic basis of this condition in dogs, we analyzed the genomes of affected and healthy individuals. Our research led us to a single gene, PAOX, which carries a missense variant likely affecting the function of polyamine oxidase and ultimately disrupting how the nerve cells function and survive. Most affected dogs had two copies of the mutant allele, while it was absent or in only one copy in healthy dogs. Additional analyses suggested that the variant may interfere with the nerves ability to maintain their structure and function properly. The mutant allele does not appear to reduce the overall level of PAOX protein, but it may affect how the protein works. Our findings provide a new genetic test that can help breeders avoid producing affected puppies. They also highlight this condition in dogs as a valuable model for understanding similar diseases in humans.

genetics↗

bioRxiv2024

Variant classification guidelines for animals to objectively evaluate genetic variant pathogenicity

Assessing the pathogenicity of a disease-associated variant in animals accurately is vital, both on a population and individual scale. At the population level, breeding decisions based on invalid DNA tests can lead to the incorrect exclusion of animals and compromise the long- term health of a population, and at the level of the individual animal, lead to incorrect treatment and even life-ending decisions. Criteria to determine pathogenicity are not standardized, hence no guidelines for animal variants are available. Here, we developed and optimized the animal variant classification guidelines, based on those developed for humans by The American College of Medical Genetics and Genomics, and demonstrated a superior classification in animals. We described methods to develop datasets for benchmarking the criteria and identified the most optimal in silico variant effect predictor tools. As the reproducibility was high, we classified 72 known disease-associated variants in cats and 40 other disease-associated variants in eight additional species.

genetics↗

bioRxiv2020

Werewolf, there wolf: variants in Hairless associated with hypotrichia and roaning in the lykoi cat breed

A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi, was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non-lykoi cats suggested two variants in the cat homolog for Hairless (HR: lysine demethylase and nuclear receptor corepressor) as candidate causal variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations.

genetics↗