Abstract
ObjectiveA group of genes have been reported to be associated with myopathies with tubular aggregates (TAs). Many cases with TAs still lack of genetic clarification. This study aims to explore the genetic background of cases with TAs in order to improve our knowledge of the pathogenesis of these rare pathological structures.MethodsThirty‐three patients including two family members with biopsy confirmed TAs were collected. Whole‐exome sequencing was performed on 31 unrelated index patients and a candidate gene search strategy was conducted. The identified variants were confirmed by Sanger sequencing. The wild‐type and the mutant p.Ala11Thr of ALG14 were transfected into human embryonic kidney 293 cells (HEK293), and western blot analysis was performed to quantify protein expression levels.ResultsEleven index cases (33%) were found to have pathogenic variant or likely pathogenic variants in STIM1, ORAI1, PGAM2, SCN4A, CASQ1 and ALG14. Among them, the c.764A>T (p.Glu255Val) in STIM1 and the c.1333G>C (p.Val445Leu) in SCN4A were novel. Western blot analysis showed that the expression of ALG14 protein was severely reduced in the mutant ALG14 HEK293 cells (p.Ala11Thr) compared with wild type. The ALG14 variants might be associated with TAs in patients with complex multisystem disorders.InterpretationThis study expands the phenotypic and genotypic spectrums of myopathies with TAs. Our findings further confirm previous hypothesis that genes related with calcium signalling pathway and N‐linked glycosylation pathway are the main genetic causes of myopathies with TAs.
Highlights
Tubular aggregates (TAs), which are unusual membranous structures in skeletal muscle, were first described in 1964.1 They are found predominantly in type II muscle fibres, they have been described in both type I and type II fibres.[2]
This study aims to explore the genetic background of cases with TAs in order to improve our knowledge of the pathogenesis of these rare pathological structures
Six patients present with eye problems (18%) including tonic pupils, ophthalmoplegia, ptosis and intermittent diplopia, three patients with involuntary movements (9%) including
Summary
Tubular aggregates (TAs), which are unusual membranous structures in skeletal muscle, were first described in 1964.1 They are found predominantly in type II muscle fibres, they have been described in both type I and type II fibres.[2] By enzyme histochemistry, TAs appear bright red with modified Gomori trichrome (mGT), and stain with periodic acid-Schiff (PAS). They react for myoadenylate deaminase (MAD), even without substrate, non-specific esterase and nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR). TAs are characterised by the abnormal accumulation of densely packed tubules of variable forms and sizes located in skeletal muscle fibres.[5]
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