Hailey-Hailey Disease: Molecular and Clinical Characterization of Novel Mutations in the ATP2C1 Gene

Abstract

Hailey-Hailey disease is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. Mutations in ATP2C1, the gene encoding a novel, P-type Ca2+-transport ATPase, were recently found to cause Hailey-Hailey disease. In this study, we used conformation-sensitive gel electrophoresis to screen all 28 translated exons of ATP2C1 in 24 Hailey-Hailey disease families and three sporadic cases with the disorder. We identified 22 different mutations, 18 of which have not previously been reported, in 25 probands. The novel mutations comprise three nonsense, six insertion/deletion, three splice-site, and six missense mutations and are distributed throughout the ATP2C1 gene. Six mutations were found in multiple families investigated here or in our previous study. Haplotype analysis revealed that two of these are recurrent mutations that have not been inherited from a common ancestor. Comparison between genotype and phenotype in 23 families failed to yield any clear correlation between the nature of the mutation and clinical features of Hailey-Hailey disease. The extensive interfamilial and intrafamilial phenotypic variability observed suggests that modifying genes and/or environmental factors may greatly influence the clinical features of this disease.

Effect of Hailey-Hailey Disease Mutations on the Function of a New Variant of Human Secretory Pathway Ca2+/Mn2+-ATPase (hSPCA1)

“…The full-length ATP2C1d cDNA was then transferred into the mammalian expression vector pMT2, with the insert corresponding to the entire coding sequence (nt 125-end) of the deposited ATP2C1d nucleotide sequence. Missense mutations originally reported in HHD patients by Sudbrak et al (2) and Dobson-Stone et al (19) were introduced into the wild type ATP2C1 expression clone using the QuikChange TM XL site-directed mutagenesis kit (Stratagene). The full-length cDNA clones were sequenced in both directions to ensure no additional sequence changes SCHEME 1.…”

“…26 of an HHD patient (19). With the likely effect of impaired splicing to exon 27, it can be inferred that hSPCA1a, hSPCA1b, and hSPCA1d cannot be produced from the mutant allele, because these splice variants contain amino acid stretches encoded by different parts of exon 27 (see Fig.…”

“…The primary aim of this study was to explore the stability and functional properties of a selected panel of mutated hSPCA1 proteins (see Table I), with each mutant incorporating one of the documented ATP2C1 missense mutations previously identified in HHD patients in our laboratory (2,19). We have chosen to assess the effect of these disease mutations when introduced into a new splice variant, ATP2C1d, described here for the first time.…”

“…We have previously described a spectrum of mutations scattered throughout the ATP2C1 gene in HHD patients (2,19). Although nonsense, frameshift, and splice-site mutations are predicted to cause nonsense-mediated mRNA decay (20) or aberrant splicing, the underlying cause of disease in patients carrying missense mutations cannot be predicted a priori.…”

Functional expression of heterologous proteins in yeast: insights into Ca2+ signaling and Ca2+-transporting ATPases

“…In summary, the results from phenotype screening of mutants are remarkably consistent with the crystal structure and constitute experimental validation of the homology models. Figure 3 depicts the location of missense and nonsense mutations in hSPCA1 identified in HHD patients (16,24,36,47,77,96). Although chain termination mutations are scattered throughout the length of the polypeptide, the missense mutations are strikingly clustered in regions of the proteins that are critical for function (Fig.…”