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Multidimensional analyses of the pathomechanism caused by the non-catalytic GNE variant, c.620A>T, in patients with GNE myopathy

التفاصيل البيبلوغرافية
العنوان: Multidimensional analyses of the pathomechanism caused by the non-catalytic GNE variant, c.620A>T, in patients with GNE myopathy
المؤلفون: Wakako Yoshioka, Aritoshi Iida, Kyuto Sonehara, Kazuki Yamamoto, Yasushi Oya, Madoka Mori-Yoshimura, Takashi Kurashige, Mariko Okubo, Megumu Ogawa, Fumihiko Matsuda, Koichiro Higasa, Shinichiro Hayashi, Harumasa Nakamura, Masakazu Sekijima, Yukinori Okada, Satoru Noguchi, Ichizo Nishino
المصدر: Scientific Reports, Vol 12, Iss 1, Pp 1-11 (2022)
بيانات النشر: Nature Portfolio, 2022.
سنة النشر: 2022
المجموعة: LCC:Medicine
LCC:Science
مصطلحات موضوعية: Medicine, Science
الوصف: Abstract 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.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2045-2322
Relation: https://doaj.org/toc/2045-2322
DOI: 10.1038/s41598-022-26419-0
URL الوصول: https://doaj.org/article/4f9dabf851b449cc98ef9808181bb5ac
رقم الأكسشن: edsdoj.4f9dabf851b449cc98ef9808181bb5ac
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:20452322
DOI:10.1038/s41598-022-26419-0