SLC25A11, a Novel Gene Associated With Carney-Stratakis Syndrome.

IF 3 Q2 ENDOCRINOLOGY & METABOLISM
Journal of the Endocrine Society Pub Date : 2025-04-02 eCollection Date: 2025-05-01 DOI:10.1210/jendso/bvaf052
Felipe Freitas-Castro, Lucas S Santana, Gustavo F C Fagundes, Eduardo C Lobato, Ana Caroline F Afonso, Izabel T Nakamura, Felipe L Ledesma, Ibere C Soares, Berenice B Mendonca, Ana Claudia Latronico, Constantine A Stratakis, Madson Q Almeida
{"title":"<i>SLC25A11</i>, a Novel Gene Associated With Carney-Stratakis Syndrome.","authors":"Felipe Freitas-Castro, Lucas S Santana, Gustavo F C Fagundes, Eduardo C Lobato, Ana Caroline F Afonso, Izabel T Nakamura, Felipe L Ledesma, Ibere C Soares, Berenice B Mendonca, Ana Claudia Latronico, Constantine A Stratakis, Madson Q Almeida","doi":"10.1210/jendso/bvaf052","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Carney-Stratakis syndrome (CSS), a rare condition characterized by paragangliomas and/or pheochromocytomas and gastrointestinal stromal tumors (GIST), is caused by germline heterozygous pathogenic variants in the succinate dehydrogenase subunit genes (<i>SDHB, SDHC, SDHD</i>).</p><p><strong>Methods: </strong>Histological, genetic, and functional analyses were conducted in a 59-year-old female with CSS (9 cm left pheochromocytoma, 4.8 cm paraganglioma, and 9.3 cm GIST). Whole-exome sequencing (WES) of germline DNA paired with tumor DNA was performed.</p><p><strong>Results: </strong>WES identified a rare heterozygous germline variant (c.293G>A/p.Arg98His) in the mitochondrial 2-oxoglutarate/malate carrier gene (<i>SLC25A11</i>). This variant, located in a highly conserved residue of the <i>SLC25A11</i> mitochondrial carrier domain, is predicted to be deleterious in silico (REVEL score = 0.81). WES of pheochromocytoma, paraganglioma, and GIST did not reveal somatic pathogenic variants in genes previously associated with these tumors. A significant reduction in <i>SLC25A11</i> expression was observed in the tumors of this patient with the <i>SLC25A11</i> c.293G>A variant (0.69 ± 0.003) compared to tumors from cluster 1 (1.39 ± 0.45; <i>P</i> = 0.0229) and cluster 2 (1.79 ± 0.71; <i>P</i> = .0154). Consistent with the mRNA findings, <i>SLC25A11</i> protein levels were markedly reduced in the pheochromocytoma and paraganglioma compared to other tumors. Negative staining for 5-hydroxymethylcytosine in all 3 tumors suggests a DNA hypermethylation profile characteristic of cluster 1A, despite normal SDHB expression levels. However, genome-wide copy number variation analysis did not reveal any loss of heterozygosity at the <i>SLC25A11</i> locus.</p><p><strong>Conclusion: </strong>The loss of SLC25A11 expression in tumors, the absence of somatic drivers, and the hypermethylation status strongly support the role of <i>SLC25A11</i> in CSS pathogenesis.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 5","pages":"bvaf052"},"PeriodicalIF":3.0000,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000648/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of the Endocrine Society","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1210/jendso/bvaf052","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Carney-Stratakis syndrome (CSS), a rare condition characterized by paragangliomas and/or pheochromocytomas and gastrointestinal stromal tumors (GIST), is caused by germline heterozygous pathogenic variants in the succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD).

Methods: Histological, genetic, and functional analyses were conducted in a 59-year-old female with CSS (9 cm left pheochromocytoma, 4.8 cm paraganglioma, and 9.3 cm GIST). Whole-exome sequencing (WES) of germline DNA paired with tumor DNA was performed.

Results: WES identified a rare heterozygous germline variant (c.293G>A/p.Arg98His) in the mitochondrial 2-oxoglutarate/malate carrier gene (SLC25A11). This variant, located in a highly conserved residue of the SLC25A11 mitochondrial carrier domain, is predicted to be deleterious in silico (REVEL score = 0.81). WES of pheochromocytoma, paraganglioma, and GIST did not reveal somatic pathogenic variants in genes previously associated with these tumors. A significant reduction in SLC25A11 expression was observed in the tumors of this patient with the SLC25A11 c.293G>A variant (0.69 ± 0.003) compared to tumors from cluster 1 (1.39 ± 0.45; P = 0.0229) and cluster 2 (1.79 ± 0.71; P = .0154). Consistent with the mRNA findings, SLC25A11 protein levels were markedly reduced in the pheochromocytoma and paraganglioma compared to other tumors. Negative staining for 5-hydroxymethylcytosine in all 3 tumors suggests a DNA hypermethylation profile characteristic of cluster 1A, despite normal SDHB expression levels. However, genome-wide copy number variation analysis did not reveal any loss of heterozygosity at the SLC25A11 locus.

Conclusion: The loss of SLC25A11 expression in tumors, the absence of somatic drivers, and the hypermethylation status strongly support the role of SLC25A11 in CSS pathogenesis.

与卡尼-斯特拉基斯综合征相关的新基因SLC25A11
背景:卡尼- stratakis综合征(CSS)是一种罕见的疾病,以副神经节瘤和/或嗜铬细胞瘤和胃肠道间质瘤(GIST)为特征,由琥珀酸脱氢酶亚基基因(SDHB, SDHC, SDHD)的种系杂合致病性变异引起。方法:对59岁女性CSS患者(左侧嗜铬细胞瘤9cm,副神经节瘤4.8 cm, GIST 9.3 cm)进行组织学、遗传学和功能分析。对种系DNA与肿瘤DNA进行全外显子组测序(WES)。结果:WES在线粒体2-氧戊二酸/苹果酸载体基因(SLC25A11)中鉴定出一种罕见的杂合种系变异(c.293G> a /p.Arg98His)。该变异位于SLC25A11线粒体载体结构域的高度保守残基上,预计在硅中是有害的(REVEL评分= 0.81)。嗜铬细胞瘤、副神经节瘤和GIST的WES未发现先前与这些肿瘤相关的基因的躯体致病变异。SLC25A11 c.293G>A变异患者的肿瘤中SLC25A11的表达显著降低(0.69±0.003),而第1类患者的肿瘤中SLC25A11的表达明显降低(1.39±0.45;P = 0.0229)和聚类2(1.79±0.71;P = .0154)。与mRNA的发现一致,与其他肿瘤相比,嗜铬细胞瘤和副神经节瘤中的SLC25A11蛋白水平显著降低。在所有3个肿瘤中,5-羟甲基胞嘧啶染色阴性表明,尽管SDHB表达水平正常,但DNA高甲基化谱具有1A簇的特征。然而,全基因组拷贝数变异分析并未显示SLC25A11位点的杂合性缺失。结论:SLC25A11在肿瘤中的表达缺失、缺乏体细胞驱动因素以及高甲基化状态有力地支持了SLC25A11在CSS发病中的作用。
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
Journal of the Endocrine Society
Journal of the Endocrine Society Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
5.50
自引率
0.00%
发文量
2039
审稿时长
9 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:604180095
Book学术官方微信