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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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.
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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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