{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T06:05:14Z","timestamp":1792908314170,"version":"4.5.0"},"reference-count":75,"publisher":"American Society for Clinical Investigation","issue":"4","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":90,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NIDDK","award":["U01DK136965,R01DK101530,R01DK119955,T32DK007217"],"award-info":[{"award-number":["U01DK136965,R01DK101530,R01DK119955,T32DK007217"]}]},{"DOI":"10.13039\/100009863","name":"Neuroendocrine Tumor Research Foundation","doi-asserted-by":"crossref","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100009863","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,16]]},"abstract":"<jats:p>\n                    Hereditary pheochromocytoma and paraganglioma (hPPGL) is caused by pathogenic mutations in succinate dehydrogenase (SDH) genes, commonly\n                    <jats:italic>SDHB<\/jats:italic>\n                    . However, over 80% of\n                    <jats:italic>SDHB<\/jats:italic>\n                    missense variants are classified as variants of uncertain significance (VUS), limiting clinical interpretation and diagnostic utility of germline testing. To provide functional evidence of SDHB allele pathogenicity or benignity, we developed a cellular complementation assay that quantifies intracellular succinate\/fumarate ratios as a readout of SDH enzymatic activity. This assay reliably distinguished pathogenic from benign alleles with high fidelity, outperforming and complementing computational predictions. Functional assessment of patient-derived VUS alleles supported reclassification of 87% of tested variants and revealed that mutations in the iron-sulfur cluster domain were amorphic, while those at or beyond the C-terminal residue Tyr273 retained function. Variants associated with Leigh syndrome retained activity, consistent with their biallelic inheritance and distinct pathogenic mechanisms from\n                    <jats:italic>SDHB<\/jats:italic>\n                    -related tumorigenesis. Notably, hypomorphic pathogenic\n                    <jats:italic>SDHB<\/jats:italic>\n                    variants correlated with increased head and neck paraganglioma occurrence, revealing a genotype-phenotype relationship. Functional characterization of\n                    <jats:italic>SDHB<\/jats:italic>\n                    missense variants supports clinical classification, informs hPPGL risk stratification, and has immediate diagnostic impact.\n                  <\/jats:p>","DOI":"10.1172\/jci198165","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T17:01:10Z","timestamp":1763485270000},"source":"Crossref","is-referenced-by-count":11,"title":["Functional characterization of SDHB variants clarifies hereditary pheochromocytoma and paraganglioma risk and genotype-phenotype relationships"],"prefix":"10.1172","volume":"136","author":[{"given":"Sooyeon","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Endocrinology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leor","family":"Needleman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology 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