Deciphering DST -associated disorders: biallelic variants affecting DST-b cause a congenital myopathy
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Le résumé fourni par la source
The dystonin gene (DST) encodes three major isoforms, DST-a, DST-b and DST-e. Biallelic pathogenic variants in DST have previously been associated with two allelic monogenic disorders: hereditary sensory and autonomic neuropathy type VI (caused by a loss of DST-a) and epidermolysis bullosa simplex 3 (caused by a loss of DST-e). We investigated patients diagnosed with congenital myopathy using exome or genome sequencing. In 19 affected individuals from 14 unrelated families, we identified nine different variants in biallelic state located in exons 40-41, specific to DST-b. Affected individuals presented with severe neonatal myopathy characterized by arthrogryposis, hypotonia and dilated cardiomyopathy. Postnatal CPAP ventilation was required in nine patients, and seven died within the first three years of life. Survivors showed an improvement of symptoms, with the oldest three patients, now over 25 years old, exhibiting normal cognition and being ambulatory. RNA analyses demonstrated that transcripts encoding DST-b are predominantly expressed in skeletal muscle, heart tissue and cultured fibroblasts, but not in brain, matching the phenotypic spectrum. Patient-derived fibroblasts exhibited reduced DST mRNA expression. Proteomic analysis confirmed a reduction of DST protein levels due to an absence of the DST-b isoform. Muscle biopsies from four patients aged 1 month to 3 years revealed mild, non-specific myopathic changes. Ultrastructural analysis in three individuals showed mild and focal myofibrillar disruption and non-specific undulating nuclear membranes, with these changes observed in two cases each. Additionally, we identified two homozygous variants affecting both DST-a and DST-b isoforms in four patients from two unrelated families; all presented with severe arthrogryposis and died intrauterine or shortly after birth. Genotype-phenotype correlation in these patients and previously published cases with respective variants resulted in the definition of a DST-associated lethal congenital contracture syndrome. Our findings demonstrate that biallelic variants exclusively affecting DST-b cause an autosomal recessive congenital myopathy. Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome. The location of the variant within DST allows for phenotype prediction. We propose redefining DST as a disease-associated gene linked to four distinct allelic disease phenotypes.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Deciphering <i>DST</i> -associated disorders: biallelic variants affecting DST-b cause a congenital myopathy
- Date Crossref
- 11/06/2025
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Institute of Human Genetics pays non établi dans la noticeStructure de recherche
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Technical University of Munich pays non établi dans la noticeUniversité ou école supérieure
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Essen University Hospital pays non établi dans la noticeOrganisme public
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University of Duisburg-Essen pays non établi dans la noticeUniversité ou école supérieure
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Helmholtz Munich pays non établi dans la noticeStructure de recherche
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Great Ormond Street Hospital Dubowitz Neuromuscular Centre pays non établi dans la noticeÉtablissement de santé
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University College London pays non établi dans la noticeUniversité ou école supérieure
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Paracelsus Medical University pays non établi dans la noticeUniversité ou école supérieure
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Salzburger Landeskliniken pays non établi dans la noticeÉtablissement de santé
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Inserm pays non établi dans la noticeOrganisme public
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Sorbonne Université pays non établi dans la noticeUniversité ou école supérieure
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Institut de Myologie pays non établi dans la noticeStructure de recherche
Institute of Human Genetics, Technical University of Munich et Essen University Hospital, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.