Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies - Archive ouverte HAL Access content directly
Journal Articles Acta Neuropathologica Communications Year : 2022

Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies

Clémence Labasse
  • Function : Author
Guy Brochier
  • Function : Author
Ana-Lia Taratuto
  • Function : Author
John Rendu
  • Function : Author
Soledad Monges
  • Function : Author
Susana Quijano-Roy
  • Function : Author
Mai Thao Bui
  • Function : Author
Anaïs Chanut
  • Function : Author
Angéline Madelaine
  • Function : Author
Emmanuelle Lacène
  • Function : Author
Helge Amthor
  • Function : Author
Laurent Servais
  • Function : Author
Marcela Erro
  • Function : Author
Maria Saccoliti
  • Function : Author
Julien Fauré
  • Function : Author
Béatrice Lannes
  • Function : Author
Vincent Laugel
  • Function : Author
Sandra Coppens
  • Function : Author
Fabiana Lubieniecki
  • Function : Author
Ana Buj Bello
  • Function : Author
Nigel Laing
  • Function : Author
Teresinha Evangelista
  • Function : Author
Norma Romero

Abstract

Abstract Nemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1 -related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation.
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Origin : Publication funded by an institution
Licence : CC BY - Attribution

Dates and versions

hal-03820052 , version 1 (02-10-2023)

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Clémence Labasse, Guy Brochier, Ana-Lia Taratuto, Bruno Cadot, John Rendu, et al.. Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies. Acta Neuropathologica Communications, 2022, 10 (1), pp.101. ⟨10.1186/s40478-022-01400-0⟩. ⟨hal-03820052⟩
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