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Dominantly inherited myosin IIa myopathy caused by aberrant splicing of MYH2

Hedberg-Oldfors, Carola ; Elíasdóttir, Ólöf ; Geijer, Mats LU ; Lindberg, Christopher and Oldfors, Anders (2022) In BMC Neurology 22(1).
Abstract

Background: Myosin heavy chain (MyHC) isoforms define the three major muscle fiber types in human extremity muscles. Slow beta/cardiac MyHC (MYH7) is expressed in type 1 muscle fibers. MyHC IIa (MYH2) and MyHC IIx (MYH1) are expressed in type 2A and 2B fibers, respectively. Whereas recessive MyHC IIa myopathy has been described in many cases, myopathy caused by dominant MYH2 variants is rare and has been described with clinical manifestations and muscle pathology in only one family and two sporadic cases. Methods: We investigated three patients from one family with a dominantly inherited myopathy by clinical investigation, whole-genome sequencing, muscle biopsy, and magnetic resonance imaging (MRI). Results: Three siblings, one woman... (More)

Background: Myosin heavy chain (MyHC) isoforms define the three major muscle fiber types in human extremity muscles. Slow beta/cardiac MyHC (MYH7) is expressed in type 1 muscle fibers. MyHC IIa (MYH2) and MyHC IIx (MYH1) are expressed in type 2A and 2B fibers, respectively. Whereas recessive MyHC IIa myopathy has been described in many cases, myopathy caused by dominant MYH2 variants is rare and has been described with clinical manifestations and muscle pathology in only one family and two sporadic cases. Methods: We investigated three patients from one family with a dominantly inherited myopathy by clinical investigation, whole-genome sequencing, muscle biopsy, and magnetic resonance imaging (MRI). Results: Three siblings, one woman and two men now 54, 56 and 66 years old, had experienced muscle weakness initially affecting the lower limbs from young adulthood. They have now generalized proximal muscle weakness affecting ambulation, but no ophthalmoplegia. Whole-genome sequencing identified a heterozygous MYH2 variant, segregating with the disease in the three affected individuals: c.5673 + 1G > C. Analysis of cDNA confirmed the predicted splicing defect with skipping of exon 39 and loss of residues 1860–1891 in the distal tail of the MyHC IIa, largely overlapping with the filament assembly region (aa1877–1905). Muscle biopsy in two of the affected individuals showed prominent type 1 muscle fiber predominance with only a few very small, scattered type 2A fibers and no type 2B fibers. The small type 2A fibers were frequently hybrid fibers with either slow MyHC or embryonic MyHC expression. The type 1 fibers showed variation in fiber size, internal nuclei and some structural alterations. There was fatty infiltration, which was also demonstrated by MRI. Conclusion: Dominantly inherited MyHC IIa myopathy due to a splice defect causing loss of amino acids 1860–1891 in the distal tail of the MyHC IIa protein including part of the assembly competence domain. The myopathy is manifesting with slowly progressive muscle weakness without overt ophthalmoplegia and markedly reduced number and size of type 2 fibers.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Autosomal dominant, MYH2, Myopathy, Myosin heavy chain, Splice-site
in
BMC Neurology
volume
22
issue
1
article number
428
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85141842985
  • pmid:36380287
ISSN
1471-2377
DOI
10.1186/s12883-022-02935-4
language
English
LU publication?
yes
id
81581878-5bee-43bb-a450-bc06ae971f87
date added to LUP
2022-12-29 11:42:02
date last changed
2024-06-15 01:17:29
@article{81581878-5bee-43bb-a450-bc06ae971f87,
  abstract     = {{<p>Background: Myosin heavy chain (MyHC) isoforms define the three major muscle fiber types in human extremity muscles. Slow beta/cardiac MyHC (MYH7) is expressed in type 1 muscle fibers. MyHC IIa (MYH2) and MyHC IIx (MYH1) are expressed in type 2A and 2B fibers, respectively. Whereas recessive MyHC IIa myopathy has been described in many cases, myopathy caused by dominant MYH2 variants is rare and has been described with clinical manifestations and muscle pathology in only one family and two sporadic cases. Methods: We investigated three patients from one family with a dominantly inherited myopathy by clinical investigation, whole-genome sequencing, muscle biopsy, and magnetic resonance imaging (MRI). Results: Three siblings, one woman and two men now 54, 56 and 66 years old, had experienced muscle weakness initially affecting the lower limbs from young adulthood. They have now generalized proximal muscle weakness affecting ambulation, but no ophthalmoplegia. Whole-genome sequencing identified a heterozygous MYH2 variant, segregating with the disease in the three affected individuals: c.5673 + 1G &gt; C. Analysis of cDNA confirmed the predicted splicing defect with skipping of exon 39 and loss of residues 1860–1891 in the distal tail of the MyHC IIa, largely overlapping with the filament assembly region (aa1877–1905). Muscle biopsy in two of the affected individuals showed prominent type 1 muscle fiber predominance with only a few very small, scattered type 2A fibers and no type 2B fibers. The small type 2A fibers were frequently hybrid fibers with either slow MyHC or embryonic MyHC expression. The type 1 fibers showed variation in fiber size, internal nuclei and some structural alterations. There was fatty infiltration, which was also demonstrated by MRI. Conclusion: Dominantly inherited MyHC IIa myopathy due to a splice defect causing loss of amino acids 1860–1891 in the distal tail of the MyHC IIa protein including part of the assembly competence domain. The myopathy is manifesting with slowly progressive muscle weakness without overt ophthalmoplegia and markedly reduced number and size of type 2 fibers.</p>}},
  author       = {{Hedberg-Oldfors, Carola and Elíasdóttir, Ólöf and Geijer, Mats and Lindberg, Christopher and Oldfors, Anders}},
  issn         = {{1471-2377}},
  keywords     = {{Autosomal dominant; MYH2; Myopathy; Myosin heavy chain; Splice-site}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{BMC Neurology}},
  title        = {{Dominantly inherited myosin IIa myopathy caused by aberrant splicing of MYH2}},
  url          = {{http://dx.doi.org/10.1186/s12883-022-02935-4}},
  doi          = {{10.1186/s12883-022-02935-4}},
  volume       = {{22}},
  year         = {{2022}},
}