Differential inclusion of NEB exons 143 and 144 provides insight into NEB-related myopathy variant interpretation and disease manifestation.

IF 3.3 Q2 GENETICS & HEREDITY
Sarah Silverstein, Rotem Orbach, Safoora Syeda, A Reghan Foley, Svetlana Gorokhova, Katherine G Meilleur, Meganne E Leach, Prech Uapinyoying, Katherine R Chao, Sandra Donkervoort, Carsten G Bönnemann
{"title":"Differential inclusion of NEB exons 143 and 144 provides insight into NEB-related myopathy variant interpretation and disease manifestation.","authors":"Sarah Silverstein, Rotem Orbach, Safoora Syeda, A Reghan Foley, Svetlana Gorokhova, Katherine G Meilleur, Meganne E Leach, Prech Uapinyoying, Katherine R Chao, Sandra Donkervoort, Carsten G Bönnemann","doi":"10.1016/j.xhgg.2024.100354","DOIUrl":null,"url":null,"abstract":"<p><p>Biallelic pathogenic variants in the gene encoding nebulin (NEB) are a known cause of congenital myopathy. We present two brothers with congenital myopathy and compound heterozygous variants (NC_000002.12:g.151692086G>T; NM_001271208.2: c.2079C>A; p.(Cys693Ter) and NC_000002.12:g.151533439T>C; NM_001271208.2:c.21522+3A>G) in NEB. Transcriptomic sequencing on affected individual muscles revealed that the extended splice variant c.21522+3A>G causes exon 144 skipping. Nebulin isoforms containing exon 144 are known to be mutually exclusive with isoforms containing exon 143, and these isoforms are differentially expressed during development and in adult skeletal muscles. Affected individuals' MRI patterns of muscle involvement were compared with the known pattern of relative abundance of these two isoforms in muscle. We propose that the pattern of muscle involvement in these affected individuals better fits the distribution of exon 144-containing isoforms in muscle than with previously published MRI findings in NEB-related disease due to other variants. Our report introduces disease pathogenesis and manifestation as a result of alteration of isoform distributions in muscle.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11525221/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"HGG Advances","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.xhgg.2024.100354","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

Abstract

Biallelic pathogenic variants in the gene encoding nebulin (NEB) are a known cause of congenital myopathy. We present two brothers with congenital myopathy and compound heterozygous variants (NC_000002.12:g.151692086G>T; NM_001271208.2: c.2079C>A; p.(Cys693Ter) and NC_000002.12:g.151533439T>C; NM_001271208.2:c.21522+3A>G) in NEB. Transcriptomic sequencing on affected individual muscles revealed that the extended splice variant c.21522+3A>G causes exon 144 skipping. Nebulin isoforms containing exon 144 are known to be mutually exclusive with isoforms containing exon 143, and these isoforms are differentially expressed during development and in adult skeletal muscles. Affected individuals' MRI patterns of muscle involvement were compared with the known pattern of relative abundance of these two isoforms in muscle. We propose that the pattern of muscle involvement in these affected individuals better fits the distribution of exon 144-containing isoforms in muscle than with previously published MRI findings in NEB-related disease due to other variants. Our report introduces disease pathogenesis and manifestation as a result of alteration of isoform distributions in muscle.

NEB 第 143 和 144 号外显子的不同包含方式为 NEB 相关肌病变异的解释和疾病表现提供了启示。
已知编码球蛋白(NEB)基因的双倍性致病变体是导致先天性肌病的原因之一。我们发现两兄弟患有先天性肌病和 NEB 复合杂合变体(NC_000002.12:g.151692086G>T; NM_001271208.2: c.2079C>A; p.(Cys693Ter) 和 NC_000002.12:g.151533439T>C; NM_001271208.2:c.21522+3A>G )。对受影响的个体肌肉进行转录组测序发现,扩展剪接变体 c.21522+3A>G 会导致 144 号外显子跳接。已知含有 144 号外显子的 Nebulin 同工型与含有 143 号外显子的同工型相互排斥,而且这些同工型在发育过程中和成年骨骼肌中的表达量不同。我们将受影响个体肌肉受累的磁共振成像模式与已知的这两种异构体在肌肉中的相对丰度模式进行了比较。我们认为,与以前发表的因其他变体导致的 NEB 相关疾病的 MRI 发现相比,这些受影响个体的肌肉受累模式更符合含外显子 144 的同工酶在肌肉中的分布。我们的报告介绍了由于肌肉中同工酶异构体分布的改变而导致的疾病发病机制和表现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
HGG Advances
HGG Advances Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
4.30
自引率
4.50%
发文量
69
审稿时长
14 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信