SDHD – Cowden disease

In a cohort of 375 PTEN‐negative Cowden syndrome-like individuals, seven germline SDHD variants were identified in ten unrelated probands, representing 13.5% of those with mitochondrial dysfunction (PMID:18678321). These heterozygous variants occurred in individuals with breast, papillary thyroid (HP:0002895), and renal cell (HP:0005584) carcinomas, mirroring core Cowden disease features. No familial segregation data were reported. A representative allele is c.149A>G (p.His50Arg) (PMID:18678321).

Cellular assays demonstrate that SDHD-Gly12Ser and His50Arg alter PTEN nuclear translocation via SRC-induced oxidation and downregulate autophagy in thyroid carcinoma lines, effects reversible by bosutinib or PTEN knockdown (PMID:25149476, PMID:28164237). However, a knock-in mouse model for SDHD-His50Arg showed normal viability, no tumor predisposition, and intact mitochondrial function, indicating non-pathogenicity of this allele in vivo (PMID:40272934).

Key Take-home: SDHD heterozygous variants occur in a subset of PTEN-negative Cowden-like patients, but clinical utility is limited by lack of segregation and conflicting in vivo evidence.

References

• American journal of human genetics • 2008 • Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. PMID:18678321
• Human molecular genetics • 2015 • Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation. PMID:25149476
• Human molecular genetics • 2017 • Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells. PMID:28164237
• Endocrine-related cancer • 2025 • In vivo and in vitro analysis of functional effects of the SDHD H50R variant. PMID:40272934

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