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Multidimensional analyses of the pathomechanism caused by the non-catalytic GNE variant, c.620A>T, in patients with GNE myopathy
GNE myopathy is a distal myopathy caused by biallelic variants in GNE, which encodes a protein involved in sialic acid biosynthesis. Compound heterozygosity of the second most frequent variant among Japanese GNE myopathy patients, GNE c.620A>T encoding p.D207V, occurs in the expected number of pa...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9758176/ https://www.ncbi.nlm.nih.gov/pubmed/36526893 http://dx.doi.org/10.1038/s41598-022-26419-0 |
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author | Yoshioka, Wakako Iida, Aritoshi Sonehara, Kyuto Yamamoto, Kazuki Oya, Yasushi Mori-Yoshimura, Madoka Kurashige, Takashi Okubo, Mariko Ogawa, Megumu Matsuda, Fumihiko Higasa, Koichiro Hayashi, Shinichiro Nakamura, Harumasa Sekijima, Masakazu Okada, Yukinori Noguchi, Satoru Nishino, Ichizo |
author_facet | Yoshioka, Wakako Iida, Aritoshi Sonehara, Kyuto Yamamoto, Kazuki Oya, Yasushi Mori-Yoshimura, Madoka Kurashige, Takashi Okubo, Mariko Ogawa, Megumu Matsuda, Fumihiko Higasa, Koichiro Hayashi, Shinichiro Nakamura, Harumasa Sekijima, Masakazu Okada, Yukinori Noguchi, Satoru Nishino, Ichizo |
author_sort | Yoshioka, Wakako |
collection | PubMed |
description | GNE myopathy is a distal myopathy caused by biallelic variants in GNE, which encodes a protein involved in sialic acid biosynthesis. Compound heterozygosity of the second most frequent variant among Japanese GNE myopathy patients, GNE c.620A>T encoding p.D207V, occurs in the expected number of patients; however, homozygotes for this variant are rare; three patients identified while 238 homozygotes are estimated to exist in Japan. The aim of this study was to elucidate the pathomechanism caused by c.620A>T. Identity-by-descent mapping indicated two distinct c.620A>T haplotypes, which were not correlated with age onset or development of myopathy. Patients homozygous for c.620A>T had mildly decreased sialylation, and no additional pathogenic variants in GNE or abnormalities in transcript structure or expression of other genes related to sialic acid biosynthesis in skeletal muscle. Structural modeling of full-length GNE dimers revealed that the variant amino acid localized close to the monomer interface, but far from catalytic sites, suggesting functions in enzymatic product transfer between the epimerase and kinase domains on GNE oligomerization. In conclusion, homozygotes for c.620A>T rarely develop myopathy, while symptoms occur in compound heterozygotes, probably because of mildly decreased sialylation, due to partial defects in oligomerization and product trafficking by the mutated GNE protein. |
format | Online Article Text |
id | pubmed-9758176 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-97581762022-12-18 Multidimensional analyses of the pathomechanism caused by the non-catalytic GNE variant, c.620A>T, in patients with GNE myopathy Yoshioka, Wakako Iida, Aritoshi Sonehara, Kyuto Yamamoto, Kazuki Oya, Yasushi Mori-Yoshimura, Madoka Kurashige, Takashi Okubo, Mariko Ogawa, Megumu Matsuda, Fumihiko Higasa, Koichiro Hayashi, Shinichiro Nakamura, Harumasa Sekijima, Masakazu Okada, Yukinori Noguchi, Satoru Nishino, Ichizo Sci Rep Article GNE myopathy is a distal myopathy caused by biallelic variants in GNE, which encodes a protein involved in sialic acid biosynthesis. Compound heterozygosity of the second most frequent variant among Japanese GNE myopathy patients, GNE c.620A>T encoding p.D207V, occurs in the expected number of patients; however, homozygotes for this variant are rare; three patients identified while 238 homozygotes are estimated to exist in Japan. The aim of this study was to elucidate the pathomechanism caused by c.620A>T. Identity-by-descent mapping indicated two distinct c.620A>T haplotypes, which were not correlated with age onset or development of myopathy. Patients homozygous for c.620A>T had mildly decreased sialylation, and no additional pathogenic variants in GNE or abnormalities in transcript structure or expression of other genes related to sialic acid biosynthesis in skeletal muscle. Structural modeling of full-length GNE dimers revealed that the variant amino acid localized close to the monomer interface, but far from catalytic sites, suggesting functions in enzymatic product transfer between the epimerase and kinase domains on GNE oligomerization. In conclusion, homozygotes for c.620A>T rarely develop myopathy, while symptoms occur in compound heterozygotes, probably because of mildly decreased sialylation, due to partial defects in oligomerization and product trafficking by the mutated GNE protein. Nature Publishing Group UK 2022-12-16 /pmc/articles/PMC9758176/ /pubmed/36526893 http://dx.doi.org/10.1038/s41598-022-26419-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yoshioka, Wakako Iida, Aritoshi Sonehara, Kyuto Yamamoto, Kazuki Oya, Yasushi Mori-Yoshimura, Madoka Kurashige, Takashi Okubo, Mariko Ogawa, Megumu Matsuda, Fumihiko Higasa, Koichiro Hayashi, Shinichiro Nakamura, Harumasa Sekijima, Masakazu Okada, Yukinori Noguchi, Satoru Nishino, Ichizo Multidimensional analyses of the pathomechanism caused by the non-catalytic GNE variant, c.620A>T, in patients with GNE myopathy |
title | Multidimensional analyses of the pathomechanism caused by the non-catalytic GNE variant, c.620A>T, in patients with GNE myopathy |
title_full | Multidimensional analyses of the pathomechanism caused by the non-catalytic GNE variant, c.620A>T, in patients with GNE myopathy |
title_fullStr | Multidimensional analyses of the pathomechanism caused by the non-catalytic GNE variant, c.620A>T, in patients with GNE myopathy |
title_full_unstemmed | Multidimensional analyses of the pathomechanism caused by the non-catalytic GNE variant, c.620A>T, in patients with GNE myopathy |
title_short | Multidimensional analyses of the pathomechanism caused by the non-catalytic GNE variant, c.620A>T, in patients with GNE myopathy |
title_sort | multidimensional analyses of the pathomechanism caused by the non-catalytic gne variant, c.620a>t, in patients with gne myopathy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9758176/ https://www.ncbi.nlm.nih.gov/pubmed/36526893 http://dx.doi.org/10.1038/s41598-022-26419-0 |
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