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Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1
OBJECTIVE: To identify the gene mutation of tubular aggregate myopathy (TAM) and gain mechanistic insight into the pathogenesis of the disorder. METHODS: We described a family affected by autosomal dominant TAM and performed exome and Sanger sequencing to identify mutations. We further analyzed the...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Wolters Kluwer
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817897/ https://www.ncbi.nlm.nih.gov/pubmed/27066587 http://dx.doi.org/10.1212/NXG.0000000000000050 |
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author | Okuma, Hidehiko Saito, Fumiaki Mitsui, Jun Hara, Yuji Hatanaka, Yuki Ikeda, Miki Shimizu, Teruo Matsumura, Kiichiro Shimizu, Jun Tsuji, Shoji Sonoo, Masahiro |
author_facet | Okuma, Hidehiko Saito, Fumiaki Mitsui, Jun Hara, Yuji Hatanaka, Yuki Ikeda, Miki Shimizu, Teruo Matsumura, Kiichiro Shimizu, Jun Tsuji, Shoji Sonoo, Masahiro |
author_sort | Okuma, Hidehiko |
collection | PubMed |
description | OBJECTIVE: To identify the gene mutation of tubular aggregate myopathy (TAM) and gain mechanistic insight into the pathogenesis of the disorder. METHODS: We described a family affected by autosomal dominant TAM and performed exome and Sanger sequencing to identify mutations. We further analyzed the functional significance of the identified mutation by expression studies and intracellular Ca(2+) measurements. RESULTS: A 42-year-old man presented with slowly progressive muscle weakness and atrophy in all 4 limbs and the trunk. Muscle biopsy and microscopic examination revealed tubular aggregates in his skeletal muscle. Genetic analysis of this family identified a novel heterozygous mutation, c.1450_1451insGA (p.Ile484ArgfsX21), in stromal interaction molecule 1 (STIM1), a Ca(2+) sensor in sarcoplasmic reticulum. We transfected cultured cells with STIM1 and demonstrated that the mutant STIM1 exhibited aggregation-like appearance in shrunk cytoplasm. Furthermore, we revealed that the intracellular Ca(2+) influx is decreased by the mutant STIM1. CONCLUSIONS: The novel mutation p.Ile484ArgfsX21 is located in the cytoplasmic C-terminal inhibitory domain (CTID) of STIM1. However, all mutations reported so far in TAM reside in the luminal N-terminal EF hand region. The aggregation-like appearance of STIM1 and the decreased intracellular Ca(2+) influx in cells transfected with CTID mutant are in sharp contrast to these previous reports. Taken together, these findings indicate that mutations of STIM1 cause TAM through the dysregulation of Ca(2+) homeostasis. |
format | Online Article Text |
id | pubmed-4817897 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Wolters Kluwer |
record_format | MEDLINE/PubMed |
spelling | pubmed-48178972016-04-08 Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1 Okuma, Hidehiko Saito, Fumiaki Mitsui, Jun Hara, Yuji Hatanaka, Yuki Ikeda, Miki Shimizu, Teruo Matsumura, Kiichiro Shimizu, Jun Tsuji, Shoji Sonoo, Masahiro Neurol Genet Article OBJECTIVE: To identify the gene mutation of tubular aggregate myopathy (TAM) and gain mechanistic insight into the pathogenesis of the disorder. METHODS: We described a family affected by autosomal dominant TAM and performed exome and Sanger sequencing to identify mutations. We further analyzed the functional significance of the identified mutation by expression studies and intracellular Ca(2+) measurements. RESULTS: A 42-year-old man presented with slowly progressive muscle weakness and atrophy in all 4 limbs and the trunk. Muscle biopsy and microscopic examination revealed tubular aggregates in his skeletal muscle. Genetic analysis of this family identified a novel heterozygous mutation, c.1450_1451insGA (p.Ile484ArgfsX21), in stromal interaction molecule 1 (STIM1), a Ca(2+) sensor in sarcoplasmic reticulum. We transfected cultured cells with STIM1 and demonstrated that the mutant STIM1 exhibited aggregation-like appearance in shrunk cytoplasm. Furthermore, we revealed that the intracellular Ca(2+) influx is decreased by the mutant STIM1. CONCLUSIONS: The novel mutation p.Ile484ArgfsX21 is located in the cytoplasmic C-terminal inhibitory domain (CTID) of STIM1. However, all mutations reported so far in TAM reside in the luminal N-terminal EF hand region. The aggregation-like appearance of STIM1 and the decreased intracellular Ca(2+) influx in cells transfected with CTID mutant are in sharp contrast to these previous reports. Taken together, these findings indicate that mutations of STIM1 cause TAM through the dysregulation of Ca(2+) homeostasis. Wolters Kluwer 2016-02-01 /pmc/articles/PMC4817897/ /pubmed/27066587 http://dx.doi.org/10.1212/NXG.0000000000000050 Text en © 2016 American Academy of Neurology This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially. |
spellingShingle | Article Okuma, Hidehiko Saito, Fumiaki Mitsui, Jun Hara, Yuji Hatanaka, Yuki Ikeda, Miki Shimizu, Teruo Matsumura, Kiichiro Shimizu, Jun Tsuji, Shoji Sonoo, Masahiro Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1 |
title | Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1 |
title_full | Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1 |
title_fullStr | Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1 |
title_full_unstemmed | Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1 |
title_short | Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1 |
title_sort | tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of stim1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817897/ https://www.ncbi.nlm.nih.gov/pubmed/27066587 http://dx.doi.org/10.1212/NXG.0000000000000050 |
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