Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype
Abstract The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proxim...
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| Format: | Article |
| Language: | English |
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BMC
2021-04-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-021-01168-9 |
| _version_ | 1818866024257159168 |
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| author | Nicolas N. Madigan Michael J. Polzin Gaofeng Cui Teerin Liewluck Mohammad H. Alsharabati Christopher J. Klein Anthony J. Windebank Georges Mer Margherita Milone |
| author_facet | Nicolas N. Madigan Michael J. Polzin Gaofeng Cui Teerin Liewluck Mohammad H. Alsharabati Christopher J. Klein Anthony J. Windebank Georges Mer Margherita Milone |
| author_sort | Nicolas N. Madigan |
| collection | DOAJ |
| description | Abstract The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. MYH2-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Additional myopathological abnormalities have included rimmed vacuoles containing small p62 positive inclusions, 15–20 nm tubulofilaments, minicores and dystrophic changes. We report an adult patient with late-pediatric onset MYH2-myopathy caused by two heterozygous pathogenic variants: c.3331C>T, p.Gln1111* predicted to result in truncation of the proximal tail region of MyHC-IIA, and c.1546T>G, p.Phe516Val, affecting a highly conserved amino acid within the highly conserved catalytic motor head relay loop. This missense variant is predicted to result in a less compact loop domain and in turn could affect the protein affinity state. The patient’s genotype is accompanied by a novel myopathological phenotype characterized by centralized large myofilamentous tangles associated with clusters of nemaline rods, and ring fibers, in addition to the previously reported rimmed vacuoles, paucity and atrophy of type 2A fibers. Electron microscopy demonstrated wide areas of disorganized myofibrils which were oriented in various planes of direction and entrapped multiple nemaline rods, as corresponding to the large tangles with rods seen on light microscopy. Nemaline rods were rarely observed also in nuclei. We speculate that the mutated MyHC-IIA may influence myofibril disorganization. While nemaline rods have been described in myopathies caused by pathogenic variants in genes encoding several sarcomeric proteins, to our knowledge, nemaline rods have not been previously described in MYH2-myopathy. |
| first_indexed | 2024-12-19T10:56:52Z |
| format | Article |
| id | doaj.art-3a44d8dc51b44329ad0732315017e487 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-19T10:56:52Z |
| publishDate | 2021-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-3a44d8dc51b44329ad0732315017e4872022-12-21T20:24:47ZengBMCActa Neuropathologica Communications2051-59602021-04-019111310.1186/s40478-021-01168-9Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotypeNicolas N. Madigan0Michael J. Polzin1Gaofeng Cui2Teerin Liewluck3Mohammad H. Alsharabati4Christopher J. Klein5Anthony J. Windebank6Georges Mer7Margherita Milone8Department of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, UnityPoint HealthDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Neurology, Mayo ClinicAbstract The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. MYH2-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Additional myopathological abnormalities have included rimmed vacuoles containing small p62 positive inclusions, 15–20 nm tubulofilaments, minicores and dystrophic changes. We report an adult patient with late-pediatric onset MYH2-myopathy caused by two heterozygous pathogenic variants: c.3331C>T, p.Gln1111* predicted to result in truncation of the proximal tail region of MyHC-IIA, and c.1546T>G, p.Phe516Val, affecting a highly conserved amino acid within the highly conserved catalytic motor head relay loop. This missense variant is predicted to result in a less compact loop domain and in turn could affect the protein affinity state. The patient’s genotype is accompanied by a novel myopathological phenotype characterized by centralized large myofilamentous tangles associated with clusters of nemaline rods, and ring fibers, in addition to the previously reported rimmed vacuoles, paucity and atrophy of type 2A fibers. Electron microscopy demonstrated wide areas of disorganized myofibrils which were oriented in various planes of direction and entrapped multiple nemaline rods, as corresponding to the large tangles with rods seen on light microscopy. Nemaline rods were rarely observed also in nuclei. We speculate that the mutated MyHC-IIA may influence myofibril disorganization. While nemaline rods have been described in myopathies caused by pathogenic variants in genes encoding several sarcomeric proteins, to our knowledge, nemaline rods have not been previously described in MYH2-myopathy.https://doi.org/10.1186/s40478-021-01168-9Congenital myopathyMYH2MyHC-IIAMyosin heavy chain IIANemaline rodsSarcomeric protein aggregation |
| spellingShingle | Nicolas N. Madigan Michael J. Polzin Gaofeng Cui Teerin Liewluck Mohammad H. Alsharabati Christopher J. Klein Anthony J. Windebank Georges Mer Margherita Milone Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype Acta Neuropathologica Communications Congenital myopathy MYH2 MyHC-IIA Myosin heavy chain IIA Nemaline rods Sarcomeric protein aggregation |
| title | Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype |
| title_full | Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype |
| title_fullStr | Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype |
| title_full_unstemmed | Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype |
| title_short | Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype |
| title_sort | filamentous tangles with nemaline rods in myh2 myopathy a novel phenotype |
| topic | Congenital myopathy MYH2 MyHC-IIA Myosin heavy chain IIA Nemaline rods Sarcomeric protein aggregation |
| url | https://doi.org/10.1186/s40478-021-01168-9 |
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