Genetic defects are common in myopathies with tubular aggregates

Abstract

Objective: A 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. Methods: Thirty-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. Results: Eleven 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. Interpretation: This 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.

Woven bone formation and mineralization by rat mesenchymal stromal cells imply increased expression of the intermediate filament desmin

“…As a result, excess calcium enters the cell leading to intracellular hypercalcemic stress, and the inability to use calcium for mineralization. Consistently, abnormal bone development, growth, and architecture occur in the targeted transgenic mouse ( 33 , 34 ) and anecdotally in cases of TAM and STRMK ( 35 , 36 ). Since in non-excitable cells DES blunts SOCE by restraining STIM1 access to ORAI1, it may act as a cytoskeletal controller of intracellular Ca 2+ , and loss of DES control over STIM1 diffusion along the endoplasmic reticulum has recently been hypothesized in the pathogenesis of TAM ( 37 ).…”

MYTHO is a novel regulator of skeletal muscle autophagy and integrity

“…4A). Tubular aggregates are usually associated with several skeletal muscle disorders 26 and are believed to derive from the expansion of the SR due to altered Ca 2+ homeostasis 27 . Consistent with this notion, we observed an increase in the number of STIM1 and SERCA2 positive fibers in muscles with MYTHO-KD (Fig.…”

“…Tubular aggregates are abnormalities characterized by the accumulation of densely packed tubules of variable forms and sizes and are believed to derive from the expansion of the sarcoplasmic reticulum (SR) due to altered Ca 2+ homeostasis 27 . Tubular aggregates are found in several skeletal muscle disorders, including myotonic dystrophy 33 , myopathies resulting from STIM1 (stromal interaction molecule 1), ORAI1 (calcium release-activated calcium modulator (1) mutations 43,44 , and dystrophies associated with mutations in glycosylation-related genes 26 . Several proteins involved in the storage and update of Ca 2+ such as SERCA1 (sarco/endoplasmic reticulum Ca 2+ ATPase), STIM1, RYR1 (ryanodine receptor 1), and sarcolumenin were identified as components of tubular aggregates 45 .…”

An in vitro assay for enzymatic studies on human ALG13/14 heterodimeric UDP-N-acetylglucosamine transferase

“…To date, a total of sixteen ALG13-CDG and nine ALG14-CDG missense mutations have been identified from patients ( de Ligt et al, 2012 ; Timal et al, 2012 ; Esposito et al, 2013 ; Judith et al, 2013 ; Smith-Packard et al, 2015 ; Dimassi et al, 2016 ; Kobayashi et al, 2016 ; Bastaki et al, 2017 ; Hamici et al, 2017 ; Schorling et al, 2017 ; Kvarnung et al, 2018 ; Ng et al, 2020 ; Alsharhan et al, 2021 ; Datta et al, 2021 ; Palombo et al, 2021 ; Gang et al, 2022 ; Katata et al, 2022 ). Among these ALG13-CDG mutations, eight are located in the N-terminal region of ALG13 that is shared by isoform 1 and 2 ( Figure 5A ), while the remaining seven mutations are located in regions unique to ALG13-iso1, and only one mutation is located in short C-terminal of isoform 2 (data not shown).…”