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Missense mutations of ACTA1 cause dominant congenital myopathy with cores
  1. A M Kaindl1,2,
  2. F Rüschendorf7,
  3. S Krause5,
  4. H-H Goebel6,
  5. K Koehler1,
  6. C Becker7,
  7. D Pongratz5,
  8. J Müller-Höcker8,
  9. P Nürnberg3,7,
  10. G Stoltenburg-Didinger4,
  11. H Lochmüller5,
  12. A Huebner1
  1. 1Children’s Hospital, Technical University Dresden, Dresden, Germany
  2. 2Department of Neuropediatrics, Charité, University Medical School Berlin, Berlin, Germany
  3. 3Institute of Medical Genetics, Charité, University Medical School Berlin, Berlin, Germany
  4. 4Institute of Neuropathology, Charité, University Medical School Berlin, Berlin, Germany
  5. 5Department of Neurology, Friedrich-Baur Institute, and Gene Center, Ludwig-Maximilians-University, Munich, Germany
  6. 6Department of Neuropathology, Johannes Gutenberg University of Mainz, Mainz, Germany
  7. 7Molecular Genetics and Gene Mapping Center, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
  8. 8Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany
  1. Correspondence to:
 Angela M. Kaindl
 Department of Neuropediatrics, Charité, University Medical School, Augustenburger Platz 1, D-13353 Berlin, Germany;

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Congenital myopathies (CM) are neuromuscular disorders classified by characteristic histopathological findings in muscle fibers. Areas devoid of oxidative enzyme activity (core lesions) are pathological hallmarks of autosomal dominant or recessive central core disease (CCD; MIM 117000) and multiminicore disease (MmD; MIM 255320). While large and solitary cores in the center and along the entire length of muscle fibers are considered typical for CCD and multiple smaller cores within muscle fibers define MmD, this classic histological distinction is complicated by the marked histological variability of core lesions.1 Minicores and central cores have been detected concomitantly as well as separately in successive muscle biopsy specimens of single patients and in myofibers of different affected family members.1–4 So far, mutations in three gene loci have been associated with core myopathies: ryanodine receptor-1 gene (RYR1; MIM 180901) in both CCD and MmD, selenoprotein N-1 gene (SEPN1; MIM 606210) in MmD, and myosin heavy chain-7 gene (MYH7; MIM 160760) in CCD.5–7

The increased number of identified genetic defects in patients with thoroughly characterised CM phenotypes has disclosed both marked phenotype and genotype variability and considerable disease overlap. The finding of cores together with rod-like lesions in muscle biopsy specimens of patients with RYR1 mutations and skeletal muscle alpha-actin gene (ACTA1; MIM 102610) mutations and in families showing linkage to chromosome 15q21–q23 indicate a phenotype overlap of core diseases and nemaline myopathy (MIM 256030).8–14 Likewise, the concurrent occurrence of cores and fingerprint bodies suggests an overlap with fingerprint body myopathy (MIM 305550).15 These findings and an absence of mutations in established gene loci in patients with clinical and histological hallmarks of core myopathy promise further genetic heterogeneity.

ACTA1 mutations are known to cause three congenital myopathies: nemaline myopathy, actin myopathy (MIM 102610), and intranuclear …

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