A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy.

IF 2.9 3区 医学 Q2 GENETICS & HEREDITY
S Rehan Ahmad, Saema Hanafi
{"title":"A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy.","authors":"S Rehan Ahmad, Saema Hanafi","doi":"10.1111/cge.14733","DOIUrl":null,"url":null,"abstract":"<p><p>Agenesis of the corpus callosum with peripheral neuropathy (ACCPN) is a rare autosomal recessive disorder characterized by malformation or absence of the corpus callosum, accompanied by progressive peripheral nerve degeneration. ACCPN is associated with mutations in the SLC12A6 gene, encoding the potassium-chloride cotransporter (also termed KCC3), which plays a crucial role in neuronal ion homeostasis. In this study, we report a novel homozygous missense variant (c.1634A>G, p.H371R) in SLC12A6, identified through exome sequencing in a male proband presenting with ACCPN symptoms, including developmental delay, hypotonia, epileptic seizures, and corpus callosal dysgenesis. The proband's MRI findings revealed additional neurodevelopmental abnormalities such as hippocampal malformation. Functional analysis showed that while the mutant SLC12A6 transcript and protein levels were comparable to wild type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion transport function. This mislocalization caused an imbalance in potassium and chloride ion levels in the proband's cells. Bioinformatics tools predicted the pathogenicity of the p.H371R mutation, and structural modeling revealed a destabilization effect. Elevated levels of cellular senescence markers, p16 and p21, were detected, indicating that ion dysregulation due to SLC12A6-p.H371R mislocalization contributed to cellular stress. This study provides novel insights into the pathogenic mechanism of ACCPN, highlighting the importance of mutant SLC12A6 mislocalization and ion homeostasis in disease progression. The identification of the p.H371R mutation adds to the spectrum of SLC12A6 mutations linked to ACCPN and underscores the potential for targeted therapeutic strategies.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cge.14733","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

Abstract

Agenesis of the corpus callosum with peripheral neuropathy (ACCPN) is a rare autosomal recessive disorder characterized by malformation or absence of the corpus callosum, accompanied by progressive peripheral nerve degeneration. ACCPN is associated with mutations in the SLC12A6 gene, encoding the potassium-chloride cotransporter (also termed KCC3), which plays a crucial role in neuronal ion homeostasis. In this study, we report a novel homozygous missense variant (c.1634A>G, p.H371R) in SLC12A6, identified through exome sequencing in a male proband presenting with ACCPN symptoms, including developmental delay, hypotonia, epileptic seizures, and corpus callosal dysgenesis. The proband's MRI findings revealed additional neurodevelopmental abnormalities such as hippocampal malformation. Functional analysis showed that while the mutant SLC12A6 transcript and protein levels were comparable to wild type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion transport function. This mislocalization caused an imbalance in potassium and chloride ion levels in the proband's cells. Bioinformatics tools predicted the pathogenicity of the p.H371R mutation, and structural modeling revealed a destabilization effect. Elevated levels of cellular senescence markers, p16 and p21, were detected, indicating that ion dysregulation due to SLC12A6-p.H371R mislocalization contributed to cellular stress. This study provides novel insights into the pathogenic mechanism of ACCPN, highlighting the importance of mutant SLC12A6 mislocalization and ion homeostasis in disease progression. The identification of the p.H371R mutation adds to the spectrum of SLC12A6 mutations linked to ACCPN and underscores the potential for targeted therapeutic strategies.

一种新的SLC12A6错义突变损害了该蛋白的离子转运功能,导致胼胝体发育不全伴周围神经病变。
胼胝体发育不全伴周围神经病变(ACCPN)是一种罕见的常染色体隐性遗传病,其特征是胼胝体畸形或缺失,并伴有进行性周围神经变性。ACCPN与SLC12A6基因突变有关,该基因编码氯化钾共转运体(也称为KCC3),在神经元离子稳态中起着至关重要的作用。在这项研究中,我们报告了SLC12A6中一个新的纯合错义变异(c.1634A b> G, p.H371R),通过外显子组测序在一个表现出ACCPN症状的男性先显子中发现,包括发育迟缓、低强直、癫痫发作和胼胝体发育不良。先证者的核磁共振结果显示了额外的神经发育异常,如海马畸形。功能分析显示,突变体SLC12A6转录本和蛋白水平与野生型相当,但突变体蛋白错定位于细胞质,破坏了其离子运输功能。这种定位错误导致先证者细胞中钾离子和氯离子水平失衡。生物信息学工具预测了p.H371R突变的致病性,结构模型显示了不稳定效应。细胞衰老标志物p16和p21水平升高,表明SLC12A6-p导致离子失调。H371R错位导致细胞应激。这项研究为ACCPN的致病机制提供了新的见解,强调了SLC12A6突变体错定位和离子稳态在疾病进展中的重要性。p.H371R突变的鉴定增加了与ACCPN相关的SLC12A6突变谱,并强调了靶向治疗策略的潜力。
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
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
×
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