AKT1 – Proteus Syndrome

Proteus syndrome is a rare mosaic overgrowth disorder caused by somatic activating variants in the AKT1 gene. Patients exhibit progressive, asymmetric postnatal overgrowth of skin, connective tissue, skeleton, and other organs, often with cerebriform connective tissue nevi, epidermal nevi, lipomas, and varicose veins. Diagnosis relies on clinical criteria supplemented by molecular detection of AKT1 mutations in affected tissues.

Genetic analyses have identified a recurrent mosaic c.49G>A (p.Glu17Lys) variant in AKT1 in over 90% of individuals meeting Proteus syndrome criteria ([PMID:23896365]). An allelic heterogeneity case report described a mosaic c.49_50delinsAG (p.Glu17Arg) variant in a patient negative for p.Glu17Lys ([PMID:32327430]). These findings establish a consistent genotype–phenotype correlation in sporadic patients.

Inheritance is exclusively postzygotic somatic mosaicism, with no evidence of germline transmission or familial segregation (affected relatives = 0). Variant detection requires deep sequencing of lesional tissue; blood often lacks the mutation due to low or absent mosaic levels.

Functionally, the p.Glu17Lys substitution broadens the PH domain’s phosphoinositide binding specificity to include PI(4,5)P₂, leading to constitutive plasma membrane localization and activation of AKT1 kinase activity. This mechanism drives localized hyperproliferation and overgrowth in mosaic tissues ([PMID:18954143]).

No studies have refuted the causal role of AKT1 variants; experimental concordance across biochemical, cellular, and clinical data is robust. The molecular diagnosis of AKT1 mosaicism now informs early diagnosis, prognostication, and emerging targeted therapies including allosteric AKT inhibitors.

Key Take-home: Somatic activating AKT1 mutations are pathognomonic for Proteus syndrome, enabling precise molecular diagnosis and opening avenues for targeted intervention.

References

• The British journal of dermatology • 1998 • Proteus syndrome: diagnosis in adulthood. PMID:9764165
• Journal of AAPOS • 2013 • Fibrous tumor of the superior oblique tendon in Proteus syndrome. PMID:23896365
• Cold Spring Harbor molecular case studies • 2020 • Allelic heterogeneity of Proteus syndrome. PMID:32327430
• Biochemistry • 2008 • Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain. PMID:18954143

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