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.