4.6 Article

Expression pattern of mitochondrial respiratory chain enzymes in skeletal muscle of patients with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant

期刊

BRAIN PATHOLOGY
卷 32, 期 4, 页码 -

出版社

WILEY
DOI: 10.1111/bpa.13038

关键词

homoplasmic mt-tRNA(Glu) variant; mitochondrial myopathy; mtDNA; reversible infantile respiratory chain deficiency; whole genome sequencing

资金

  1. Swedish Research Council [2018-02821]
  2. ALF agreement grants [ALFGBG-716821, ALFGBG-718681]
  3. Swedish Research Council [2018-02821] Funding Source: Swedish Research Council
  4. Vinnova [2018-02821] Funding Source: Vinnova

向作者/读者索取更多资源

This study investigated mitochondrial myopathy patients with the homoplasmic m.14674T>C variant, showing early onset of hypotonia and feeding difficulties, muscle histopathology characterized by lipid accumulation and mitochondrial proliferation. Immunoblotting and immunohistochemistry revealed significant deficiency in complex I subunit NDUFB8 and reduced expression of complex IV subunit MTCO1. Longitudinal follow-up data indicated the progressive nature of the disease.
Two homoplasmic variants in tRNA(Glu) (m.14674T>C/G) are associated with reversible infantile respiratory chain deficiency. This study sought to further characterize the expression of the individual mitochondrial respiratory chain complexes and to describe the natural history of the disease. Seven patients from four families with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant were investigated. All patients underwent skeletal muscle biopsy and mtDNA sequencing. Whole-genome sequencing was performed in one family. Western blot and immunohistochemical analyses were used to characterize the expression of the individual respiratory chain complexes. Patients presented with hypotonia and feeding difficulties within the first weeks or months of life, except for one patient who first showed symptoms at 4 years of age. Histopathological findings in muscle included lipid accumulation, numerous COX-deficient fibers, and mitochondrial proliferation. Ultrastructural abnormalities included enlarged mitochondria with concentric cristae and dense mitochondrial matrix. The m.14674T>C variant in MT-TE was identified in all patients. Immunohistochemistry and immunoblotting demonstrated pronounced deficiency of the complex I subunit NDUFB8. The expression of MTCO1, a complex IV subunit, was also decreased, but not to the same extent as NDUFB8. Longitudinal follow-up data demonstrated that not all features of the disorder are entirely transient, that the disease may be progressive, and that signs and symptoms of myopathy may develop during childhood. This study sheds new light on the involvement of complex I in reversible infantile respiratory chain deficiency, it shows that the disorder may be progressive, and that myopathy can develop without an infantile episode.

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