ATP2C1 – Hailey-Hailey Disease

Hailey-Hailey disease (HHD) is a rare autosomal dominant genodermatosis caused by heterozygous mutations in ATP2C1, which encodes the secretory pathway Ca2+/Mn2+-ATPase SPCA1 (PMID:10767338). Clinically, HHD manifests with recurrent erosions, flaccid blisters, and crusted plaques predominantly in intertriginous areas, reflecting acantholysis and impaired keratinocyte adhesion (PMID:38789364).

Genetic analyses have identified over 200 distinct ATP2C1 variants—including nonsense (e.g., c.2416C>T (p.Arg806Ter)), frameshift, splice-site, and missense mutations—across multiple ethnic cohorts, with strong segregation in more than 100 unrelated families (PMID:10767338; PMID:11841554). One recurrent variant, c.2395C>T (p.Arg799Ter), has been observed in diverse populations, underscoring allelic heterogeneity without clear genotype-phenotype correlation.

Functional studies demonstrate that HHD-associated ATP2C1 mutations result in SPCA1 haploinsufficiency and defective Golgi Ca2+/Mn2+ transport. Mutant proteins such as p.Ile580Val display impaired ion pumping, whereas others (e.g., p.Ala528Pro) show reduced stability and misfolding, consistent with a loss-of-function mechanism (PMID:12707275). Yeast and mammalian cell models confirm that SPCA1 deficiency perturbs intracellular calcium homeostasis and desmosome assembly, recapitulating human acantholysis.

The prevalence of HHD is estimated at ~1:50,000, with complete penetrance and variable expressivity influenced by environmental triggers (heat, friction, infections) (PMID:38789364). Histopathology shows suprabasal clefting and dilapidated brick-wall acantholysis, while adnexal sparing aids in differentiation from pemphigus vulgaris.

Collectively, the consistent identification of ATP2C1 mutations in >200 probands, segregation in multiplex pedigrees, and robust functional concordance between human and model systems support a Definitive gene-disease relationship. ATP2C1 testing informs diagnosis, genetic counseling, and potential development of targeted calcium-modulating therapies.

Key Take-home: ATP2C1 haploinsufficiency underlies autosomal dominant Hailey-Hailey disease, with broad allelic heterogeneity and clear clinical utility for molecular diagnosis and family counseling.

References

• Human molecular genetics • 2000 • Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump PMID:10767338
• The Journal of investigative dermatology • 2002 • Hailey-Hailey disease: molecular and clinical characterization of novel mutations in the ATP2C1 gene PMID:11841554
• The Journal of biological chemistry • 2003 • Effect of Hailey-Hailey Disease mutations on the function of a new variant of human secretory pathway Ca2+/Mn2+-ATPase (hSPCA1) PMID:12707275
• Anais brasileiros de dermatologia • 2024 • Hailey-Hailey disease: clinical, diagnostic and therapeutic update PMID:38789364

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