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Cowden disease is an autosomal dominant hamartoma syndrome characterized by multiple benign and malignant tumors of the breast, thyroid, and skin. Heterozygous germline mutations in the tumor suppressor gene PTEN account for the majority of cases, but a subset of PTEN-negative patients harbor mutations in other components of the PI3K/AKT pathway. Genetic testing of 91 unrelated Cowden syndrome and Cowden-like individuals without PTEN mutations identified AKT1 variants in 2 probands, supporting AKT1 as a rare susceptibility gene for Cowden disease ([PMID:23246288]).
Both identified AKT1 variants are missense changes: c.73C>T (p.Arg25Cys) and c.1303A>C (p.Thr435Pro), occurring in the pleckstrin homology (PH) domain and kinase domain respectively, consistent with gain-of-function effects. No additional familial segregation data were reported, and these variants were absent from PTEN-mutant cohorts.
Functional assays demonstrate that expression of these germline AKT1 variants leads to increased phosphorylation at Thr308 and elevated cellular PIP3, mirroring the downstream effects of PTEN loss and confirming a constitutive activation mechanism ([PMID:23246288]). The biochemical activation of AKT1 is concordant with the pathogenesis of Cowden disease, in which aberrant PI3K/AKT signaling drives tissue overgrowth and tumorigenesis.
Together, limited genetic evidence from two unrelated probands and concordant functional data support a Limited clinical validity for AKT1 in Cowden disease. Larger cohorts and familial segregation studies are required to elevate this association. Nonetheless, AKT1 testing may be considered in PTEN‐negative patients with Cowden or Cowden‐like phenotypes to inform surveillance and targeted therapy decisions.
Key Take-home: Germline gain-of-function AKT1 variants underlie a rare subset of Cowden disease, linking constitutive AKT activation to hamartoma formation.
Gene–Disease AssociationLimited2 probands with heterozygous AKT1 variants identified in Cowden and Cowden-like syndrome cohort ([PMID:23246288]). Genetic EvidenceLimitedTwo unrelated probands with germline AKT1 variants; variant detection did not meet quantitative threshold for strong genetic evidence ([PMID:23246288]). Functional EvidenceLimitedIn vitro studies demonstrate germline AKT1 variants increase AKT phosphorylation (P-Thr308) and PIP3 levels consistent with gain-of-function mechanism ([PMID:23246288]). |