ATP2A2 – Darier Disease

Darier disease is a rare autosomal dominant genodermatosis characterized by hyperkeratotic papules, acantholysis and dyskeratosis in seborrheic areas. It is caused by heterozygous mutations in ATP2A2, which encodes the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase isoform 2 (SERCA2), leading to disrupted calcium homeostasis in keratinocytes (PMID:12925205). The disease typically manifests in the first or second decade and shows complete penetrance with variable expressivity.

Genetic studies in 19 multiplex families and six sporadic cases identified 24 novel ATP2A2 mutations scattered throughout the 21 exons (PMID:10441323). Over half (54%) of these alterations produce premature termination codons, while 38% are non-conservative missense changes at conserved residues. Additional sequencing in independent cohorts has expanded the mutational spectrum to >150 distinct variants, including splice-site, frameshift, insertion and deletion alleles.

The inheritance is autosomal dominant, with heterozygous ATP2A2 mutations co-segregating with disease in multiple pedigrees. Segregation analysis across 19 families delineates clear linkage of ATP2A2 variants to affected relatives (PMID:10441323). Clinical heterogeneity among relatives underscores the influence of modifying factors beyond the primary mutation.

The variant spectrum encompasses missense (e.g., c.160A>G (p.Ile54Val)), nonsense, splice-site (IVS20–6T>A), and frameshift alleles, without evident hotspots. Recurrent mutations arise in specific populations (founder effects), but most variants are private to individual families. Allelic diversity correlates poorly with phenotype severity, supporting a threshold model of SERCA2 dysfunction.

Functional assays demonstrate that mutant SERCA2b proteins undergo misfolding, form insoluble aggregates, elicit endoplasmic reticulum stress, and often exert dominant-negative effects on wild-type pump function (PMID:22045735; PMID:12670936). Haploinsufficiency of SERCA2b is the predominant pathogenic mechanism, resulting in reduced calcium reuptake and impaired desmosomal assembly in keratinocytes.

Collectively, the comprehensive genetic and experimental evidence establishes a Definitive association between ATP2A2 and Darier disease, enabling accurate molecular diagnosis, variant interpretation for clinical management, and informing future therapeutic development. Key take-home: ATP2A2 mutation testing is essential for confirming Darier disease and guiding family counseling.

References

• Human Molecular Genetics • 1999 • Spectrum of novel ATP2A2 mutations in patients with Darier's disease PMID:10441323
• The Journal of Investigative Dermatology • 2003 • Mutations in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase isoform cause Darier's disease PMID:12925205
• Journal of Cell Science • 2011 • Protein aggregation of SERCA2 mutants associated with Darier disease elicits ER stress and apoptosis in keratinocytes PMID:22045735
• The Journal of Biological Chemistry • 2003 • Multiple effects of SERCA2b mutations associated with Darier's disease PMID:12670936

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