ATP2A2 – Acrokeratosis Verruciformis of Hopf

Acrokeratosis verruciformis of Hopf (AKV) is a rare autosomal dominant genodermatosis characterized by multiple flat-topped, skin-colored papules predominantly on the dorsal hands and feet. Mutations in ATP2A2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase 2 (SERCA2), underlie both Darier disease and its allelic variant AKV, which presents a distinct clinical phenotype.

Genetic evidence began with the identification of a heterozygous NM_170665.4:c.1805C>T (p.Pro602Leu) mutation co-segregating with AKV in a six-generation pedigree, demonstrating autosomal dominant inheritance and absence in 50 controls (PMID:12542527). This variant recurred in an independent kindred of 14 affected members, further confirming segregation and allelism to Darier disease (PMID:22814319). A third family study likewise reported the p.Pro602Leu alteration in AKV without overlapping Darier features (PMID:28498512).

Case reports of late-onset, non-familial AKV highlight variable expressivity and underscore ATP2A2’s role in disease diagnosis even in sporadic presentations (PMID:31696902). Conversely, mutation screening in Chinese AKV cohorts revealed no ATP2A2 defects in two families and a sporadic case, indicating locus heterogeneity and suggesting additional genetic contributors in certain populations (PMID:16716163).

Functional assays of the p.Pro602Leu mutant demonstrate loss of Ca2+ transport activity, supporting a loss-of-function mechanism consistent with haploinsufficiency observed in Darier disease. This functional concordance reinforces the pathogenicity of the ATP2A2 variant in AKV (PMID:12542527).

Despite evidence of genetic heterogeneity, the recurrent c.1805C>T (p.Pro602Leu) variant in ATP2A2 establishes a robust gene–disease association for AKV. Familial segregation, locus-specific mutational recurrence, and mechanistic data collectively support a Strong clinical validity classification.

Key Take-home: Identification of ATP2A2 c.1805C>T (p.Pro602Leu) provides a definitive molecular diagnostic marker for AKV, informs risk-based family screening, and guides development of targeted therapeutic approaches.

References

• The Journal of investigative dermatology • 2003 • Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier’s disease. PMID:12542527
• The American Journal of dermatopathology • 2012 • Acrokeratosis verruciformis of Hopf showing P602L mutation in ATP2A2 and overlapping histopathological features with Darier disease. PMID:22814319
• American journal of medical genetics. Part A • 2017 • Recurrent ATP2A2 p.(Pro602Leu) mutation differentiates Acrokeratosis verruciformis of Hopf from the allelic condition Darier disease. PMID:28498512
• Clinical and experimental dermatology • 2006 • Genetic heterogeneity in acrokeratosis verruciformis of Hopf. PMID:16716163

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