SDHAF2 – SDHAF2-Associated Paraganglioma

SDHAF2 encodes succinate dehydrogenase assembly factor 2, critical for flavinylation of SDHA in mitochondrial complex II (Gene Symbol). Germline variants in SDHAF2 predispose to paraganglioma (PGL) through loss of SDH function and pseudohypoxia signaling (Disease Name).

Inheritance follows an autosomal dominant pattern with paternal imprinting. The first evidence emerged from a large Dutch kindred harboring SDHAF2 c.232G>A (p.Gly78Arg), co-segregating in multiple affected individuals (n ≥ 3) ([PMID:20071235]). A second Spanish family exhibited the identical variant in two sisters with head and neck PGL ([PMID:20071235]). A separate case reported a likely pathogenic nonsense variant c.347G>A (p.Trp116Ter) in a 30-year-old female proband and two sisters with carotid body PGL ([PMID:31687641]).

Population studies of 104 sporadic pheochromocytomas and paragangliomas found no SDHAF2 mutations, underscoring rarity and locus heterogeneity ([PMID:20130071]). Likewise, multicenter analysis of 315 patients without SDHB/SDHC/SDHD variants identified SDHAF2 mutations in only a single young-onset PGL kindred ([PMID:20071235]).

Functional assays demonstrate that p.Gly78Arg impairs SDHA flavinylation and destabilizes SDHAF2 via LON-mediated degradation, disrupting complex II assembly in yeast and human mitochondria ([PMID:24414418]). CRISPR/Cas9 knockout of SDHAF2 in HeLa cells yields marked reductions in SDH and cytochrome c oxidase activities, confirming a dual role in respiratory chain assembly ([PMID:39237068]).

No conflicting genetic evidence has been reported; SDHAF2 mutations appear exclusive to head and neck PGL and unobserved in other tumor types or in large cohorts of sporadic cases.

Integration of genetic segregation in two unrelated families, rare LoF and missense alleles, and concordant mechanistic studies support a Moderate clinical validity for SDHAF2 in paraganglioma susceptibility. SDHAF2 testing is recommended in young patients with isolated head and neck PGL negative for other SDHx genes. Key Take-home: SDHAF2 germline variants cause autosomal dominant paraganglioma via impaired SDH assembly, guiding targeted genetic screening and surveillance.

References

• The Lancet. Oncology • 2010 • SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. PMID:20071235
• The Journal of the Endocrine Society • 2019 • A Family With a Carotid Body Paraganglioma and Thyroid Neoplasias With a New SDHAF2 Germline Variant. PMID:31687641
• The Journal of clinical endocrinology and metabolism • 2010 • Mutations of the metabolic genes IDH1, IDH2, and SDHAF2 are not major determinants of the pseudohypoxic phenotype of sporadic pheochromocytomas and paragangliomas. PMID:20130071
• FASEB journal • 2014 • Mitochondrial matrix proteostasis is linked to hereditary paraganglioma: LON-mediated turnover of the human flavinylation factor SDH5 is regulated by its interaction with SDHA. PMID:24414418
• Mitochondrion • 2024 • SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies. PMID:39237068

Evidence Based Scoring (AI generated)