Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm

Purpose Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. Methods We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. Results We identified five functional variants inTHSD4of which two heterozygous variants lead to a premature termination codon.THSD4encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. TheTHSD4variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils.Thsd4(+/-)mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying aTHSD4variant and fromThsd4(+/-)mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. Conclusion These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies

Genetic factors reponsible of clinical variability in familial forms of thoracic aortic aneurysm

Le syndrome de Marfan (MFS) est une maladie génétique rare (1/5000 sujets), à transmission autosomique dominante. Ce syndrome est principalement dû à des mutations dans le gène codant pour la fibrilline 1 (FBN1). L’atteinte est plurisystémique touchant notamment le système cardio-vasculaire (anévrisme de l’aorte thoracique ascendante avec risque de dissection aortique). Ce syndrome est caractérisé par une très grande variabilité clinique, inter- et intrafamiliale, concernant aussi bien l’âge d’apparition des symptômes que l’évolution, la gravité ou le nombre de systèmes atteints. Toutefois, l’architecture génétique qui sous-tend la variabilité d’expression du MFS est encore inconnue. L’étape d’initiation de la maladie est sous-tendue par un modèle monogénique classique dont nous avons poursuivi l’exploration de l’hétérogénéité génétique. Dans ce modèle d’architecture, de nouveaux gènes de TAA ont été recherchés par la stratégie de WES, au sein de familles TAA sans base moléculaire connue. Un nouveau gène candidat codant pour une protéine de la famille des ADAMTS a été identifié et est en cours de validation fonctionnelle. De plus, les travaux de l’équipe ont démontré que la sévérité de la maladie était liée à des facteurs génétiques modificateurs associés à plusieurs architectures (monogénisme et corrélation génotype-phénotype, digénisme, modèle multifactoriel) dont nous avons poursuivi l’exploration. Ces études ont fait appel à une stratégie innovante qui a permis d’identifier plusieurs modèles d’architectures au-delà de la simple hétérogénéité génétique.Marfan syndrome (MFS ; OMIM #154700) is an autosomal dominant connective tissue disorder with an estimated prevalence of 1/5000 individual. It is a multisystemic disease that affects the ocular, skeletal, and cardiovascular system as well as lung, skin, and dura. Thoracic aortic aneurysm (TAA) is the main cardiovascular feature that can lead to dissection or rupture of the aortic wall, the major life-threatening event in MFS. In most cases, MFS is due to mutation in the FBN1 gene encoding fibrillin-1, an extracellular matrix protein. MFS patients display great phenotypic variability, for age of onset as well as severity and number of clinical manifestations. However, the genetic architecture underlying this clinical variability is still unknown. A monogenic model underlies the disease initiation step. Therefore, we continue to investigate the genetic heterogeneity of the pathology. In this architecture model, new TAA genes have been sought. In this purpose, TAA families without mutation in the known genes have been explored by the WES strategy. A new candidate gene encoding a protein of the ADAMTS family has been identified and is currently under investigation. In addition, the team's work demonstrated that the severity of the disease was linked to modifying genetic factors associated with several architectures (monogenism and genotype-phenotype correlation, digenism, multifactorial model) that we continued to explore. These studies used an innovative strategy that identified several architectural models beyond genetic heterogeneity

À la recherche de facteurs génétiques modificateurs dans les cardiomyopathies

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The 2021 version of the gene table of neuromuscular disorders (nuclear genome)

International audienceThis table is published annually in the December issue. Its purpose is to provide the reader of Neuromuscular Disorders with an updated list of monogenic neuromuscular diseases due to a primary defect residing in the nuclear genome. It comprises diseases in which the causative gene is known or at least localized on a chromosome, if not yet identified. Diseases for which the locus has not been mapped or which are due to defects involving mitochondrial genes are not included

The 2024 version of the gene table of neuromuscular disorders (nuclear genome)

International audienc

The 2020 version of the gene table of neuromuscular disorders (nuclear genome)

International audienc

Lamin A/C Assembly Defects in LMNA-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery-Dreifuss Muscular Dystrophy

LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance to mechanical stress and gene regulation. LMNA mutations are responsible for a wide variety of pathologies, including Emery-Dreifuss (EDMD) and LMNA-related congenital muscular dystrophies (L-CMD) without clear genotype-phenotype correlations. Both diseases presented with striated muscle disorders although L-CMD symptoms appear much earlier and are more severe. Seeking for pathomechanical differences to explain the severity of L-CMD mutations, we performed an in silico analysis of the UMD-LMNA database and found that L-CMD mutations mainly affect residues involved in Lamin dimer and tetramer stability. In line with this, we found increased nucleoplasmic Lamin A/C in L-CMD patient fibroblasts and mouse myoblasts compared to the control and EDMD. L-CMD myoblasts show differentiation defects linked to their inability to upregulate muscle specific nuclear envelope (NE) proteins expression. NE proteins were mislocalized, leading to misshapen nuclei. We conclude that these defects are due to both the absence of Lamin A/C from the nuclear lamina and its maintenance in the nucleoplasm of myotubes