TRPM4 – Erythrokeratodermia Variabilis

Transient receptor potential melastatin member 4 (TRPM4) has been implicated in autosomal dominant erythrokeratodermia variabilis (Erythrokeratodermia Variabilis). Based on three unrelated probands in three families demonstrating consistent segregation and concordant functional data, the overall ClinGen clinical validity is deemed Moderate.

Genetic evidence includes two recurrent missense variants—c.3099C>G (p.Ile1033Met) and c.3119T>C (p.Ile1040Thr)—identified in three independent probands with autosomal dominant inheritance and familial co-segregation ([PMID:30528822]). These variants localize to the S6 transmembrane domain of TRPM4 and were absent from population controls. The genetic evidence meets the ClinGen Moderate tier for variant counts and segregation.

Functional assays of the TRPM4 activation gate mutants demonstrate pronounced baseline channel activity, enhanced Ca2+ sensitivity, and elevated resting membrane potential in electrophysiological recordings. Keratinocytes overexpressing p.Ile1033Met or p.Ile1040Thr show increased proliferation and up-regulation of differentiation markers, supporting a gain-of-function mechanism consistent with disease pathology. This evidence supports a ClinGen Moderate functional evidence tier ([PMID:30528822]).

In a CRISPR/Cas9 mouse model harboring the equivalent I1029M mutation, homozygous mice display heightened susceptibility to imiquimod-induced psoriasiform dermatitis characterized by increased CCR6+ γδ T cells and elevated Il17a expression, further corroborating TRPM4 gain-of-function in skin inflammation ([PMID:36341417]).

No conflicting reports have refuted the TRPM4–EKV association. Integration of genetic and experimental data supports a pathogenic role for TRPM4 GoF variants in erythrokeratodermia variabilis.

Key Take-home: Gain-of-function TRPM4 variants c.3099C>G (p.Ile1033Met) and c.3119T>C (p.Ile1040Thr) underlie autosomal dominant erythrokeratodermia variabilis, with robust genetic segregation and functional concordance informing diagnostic decision-making.

References

• The Journal of investigative dermatology • 2019 • Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia PMID:30528822
• Frontiers in immunology • 2022 • Gain-of-function of TRPM4 predisposes mice to psoriasiform dermatitis PMID:36341417

Evidence Based Scoring (AI generated)