Hailey- Hailey Disease.com
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Hailey- Hailey Disease.com
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Alternative
titles; symbols ATPase, Ca(2+)-SEQUESTERINGGene map locus 3q21-q24 (Specifically 3q22.1) TEXTHailey-Hailey disease (HHD; 169600)
is an autosomal dominant disorder characterized by persistent blisters and
erosions of the skin. By family linkage studies, the HHD region was localized to
3q21-q24. Study of a family carrying a deletion helped narrow the location. Hu
et al. (2000)(3) constructed a YAC/BAC contig from the centromeric breakpoint of
the deletion to D3S1587, an interval of approximately 1.3 Mb. Within this region
was found to reside an EST sequence that had been annotated as homologous to a
yeast gene encoding a calcium ATPase. Because that gene was predicted to have a
function related to that of SERCA2 (ATP2A2; 108740),
Hu et al. (2000)(3) isolated a full-length cDNA. Similar to other Ca(2+) ATPase
genes, this gene encodes 2 alternatively spliced transcripts, ATP2C1a and
ATP2C1b. These transcripts differed in their C termini (encoding amino acids 877
to the end), but had the same expression patterns in all tissues examined.
ATP2C1a was predicted to encode 919 amino acids, and ATP2C1b was predicted to
encode 888 amino acids. The protein encoded by ATP2C1 was highly homologous (97%
identity) to rat Pmr1, which in turn is homologous to the yeast calcium pump
Pmr1, but less homologous to other calcium pumps. ATP2C1 is highly expressed in
human epidermal keratinocytes and at various levels in other human tissues.
Patients with HHD are not known to have extracutaneous manifestations of the
disease. Hu et al. (2000)(3) found no differences in ATP2C1 mRNA levels between
skin taken from the axilla and skin from the buttock (sites particularly prone
vs resistant to blistering, respectively, in HHD patients) of one normal
individual and little change in ATP2C1 mRNA levels in normal human epidermal
keratinocytes cultured with glucocorticoid.
To screen HHD patients for ATP2C1 mutations, Hu et al. (2000)(3) identified
intron sites by comparison of genomic and cDNA sequences, designed primers
flanking the 27 identified exons, and assessed PCR products from patients and
controls by single-strand conformation polymorphism (SSCP) or
conformation-sensitive gel electrophoresis (CSGE) analyses. Among 51 unrelated
kindreds of European descent and 10 of Japanese descent, they identified 21
abnormalities (16/51 and 5/10). Of the abnormal sequences, 6 predicted single
amino acid substitutions, 2 predicted aberrant splicing, and 13 predicted
prematurely truncated products through frameshifts or single-basepair
substitution. A high frequency of the last type of mutation supported a
haploinsufficiency pathogenesis consistent with the complete deletion of the
gene in 1 kindred and further suggested that calcium pumps of the PMR1 family
function as monomers. The mechanism by which mutant ATPC1 causes acantholysis is
unknown, but it may be through abnormally elevated cytoplasmic calcium or
abnormally low Golgi Ca(2+) levels. Elevated cytoplasmic calcium might act by
altering posttranslational modification of proteins or by inducing changes in
gene expression.
Sudbrak et al. (2000)(6) identified 13 different mutations, including
nonsense, frameshift insertion and deletions, splice-site mutations, and
nonconservative missense mutations, in ATP2C1 in patients with Hailey-Hailey
disease. The identification of ATP2A2 as the gene defective in Darier disease (124200)
provided further evidence of the critical role of Ca(2+) signaling in
maintaining epidermal integrity.
Ikeda et al. (2001)(4) reported ATP2C1 mutations in 11 Japanese patients with
Hailey-Hailey disease. Some affected individuals had unique clinical features
(generalization of Hailey-Hailey disease and generalized skin eruption
resembling keratotic papules in Darier disease), but other affected individuals
did not, suggesting the presence of intrafamilial phenotypic variations. These
findings reinforced the conclusion that differences in clinical phenotypes in
Hailey-Hailey disease are probably related to factors other than the type of
causative mutation.
Chao et al. (2002)(1) identified 7 different ATP2C1 mutations, 6 of them novel, in 7 Taiwanese kindreds with Hailey-Hailey disease. They found 3 deletion mutations, 2 nonsense mutations, 1 missense mutation, and 1 splicing mutation. Dobson-Stone et al. (2002)(2) screened all 28 translated exons of ATP2C1 in
24 Hailey-Hailey disease families and 3 sporadic cases and identified 22
mutations (18 novel) in 25 probands. The novel mutations comprised 3 nonsense, 6
insertion/deletion, 3 splice site, and 6 missense mutations, and were
distributed throughout the ATP2C1 gene. They noted that 6 of the mutations were
found in multiple families in their study as well as in the studies of Sudbrak
et al. (2000)(6) and Hu et al. (2000)(3). Haplotype analysis revealed that 2 of
these were recurrent mutations. 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 inter-
and intrafamilial phenotypic variability suggested that modifying genes and/or
environmental factors may greatly influence the clinical features of this
disease.
In a patient with unilateral segmental exacerbations of Hailey-Hailey
disease, Poblete-Gutierrez et al. (2004)(5) identified heterozygosity for a
splice site mutation in exon 22 of the ATP2C1 gene (604384.0009).
Haplotype analysis of the more severely affected segmental skin regions revealed
consistent loss of the paternal wildtype allele, confirming the authors'
hypothesis that such segmental exacerbations represent a form of mosaicism with
hemizygosity for the mutation.
ALLELIC VARIANTS
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