SLC25A11, a Novel Gene Associated With Carney-Stratakis Syndrome

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Freitas-Castro, Felipe ; Santana, Lucas S. ; Fagundes, Gustavo F. C. ; Lobato, Eduardo C. ; Afonso, Ana Caroline F. ; Nakamura, Izabel T. ; Ledesma, Felipe L. ; Soares, Ibere C. ; Mendonca, Berenice B. ; Latronico, Ana Claudia ; Stratakis, Constantine A. ; Almeida, Madson Q.

• Document type: Journal article
• Source: JOURNAL OF THE ENDOCRINE SOCIETY; v. 9, n. 5, p. 9-pg., 2025-05-01.

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. (AU)

• FAPESP's process: 19/15873-6 - Investigation of new genetic, clinical and pathological aspects of endocrine arterial hypertension
• Grantee: Madson Queiroz Almeida
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/10363-0 - Whole exome sequencing for investigation of novel genetic causes of primary Aldosteronism caused by bilateral adrenal hyperplasia
• Grantee: Lucas Santos de Santana
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 24/03610-9 - Investigation of pathogenic variants in KCNJ5, ATP1A1, ATP2B3 and CTNNB1 genes in aldosteronomas.
• Grantee: Izabel Tomie Nakamura
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 21/11240-9 - Whole exome sequencing for the investigation of novel genetic causes of metastatic Pheochromocytomas and Paragangliomas
• Grantee: Felipe Freitas de Castro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral