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*604384 |
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ATPase, Ca(2+)-TRANSPORTING, TYPE 2C, MEMBER 1; ATP2C1 |
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Alternative titles; symbols |
ATPase, Ca(2+)-SEQUESTERING
SECRETORY PATHWAY Ca(2+) ATPase 1; SPCA1 |
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HGNC Approved Gene Symbol: ATP2C1 |
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Cytogenetic location: 3q22.1
Genomic
coordinates (GRCh37): 3:130,569,368
- 130,735,555 (from
NCBI) |
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Gene Phenotype Relationships |
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Location |
Phenotype |
Phenotype
MIM number |
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3q22.1 |
Hailey-Hailey disease |
169600 |
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TEXT |
Hailey-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) 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) 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) 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) 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) 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) 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) 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) 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) and Hu
et al. (2000). 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) 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. |
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ALLELIC VARIANTS (Selected
Examples): |
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Table View |
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.0001 HAILEY-HAILEY
DISEASE |
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ATP2C1, 4-BP INS, 767CCCT |
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In a family with Hailey-Hailey disease (169600), Hu
et al. (2000) found a
4-bp insertion after nucleotide 767 in exon 10 of the ATP2C1 gene.
The insertion resulted in a frameshift with a premature termination
codon 42 amino acids downstream of the mutation. |
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.0002 HAILEY-HAILEY
DISEASE |
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ATP2C1, ALA304THR |
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In a family with Hailey-Hailey disease (169600), Hu
et al. (2000) identified
a G-to-T transversion of nucleotide 910 of the ATP2C1 gene,
resulting in an ala304-to-thr amino acid substitution. |
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.0003 HAILEY-HAILEY
DISEASE |
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ATP2C1, ARG468TER |
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In a family with Hailey-Hailey disease (169600), Hu
et al. (2000) found a
1402C-T transition in the ATP2C1 gene that altered codon 468 from
arginine to stop. |
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.0004 HAILEY-HAILEY
DISEASE |
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ATP2C1, 4-BP DEL, 2374TTTG |
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In 2 unrelated families with Hailey-Hailey disease (169600), Hu
et al. (2000) found
an identical 4-bp deletion of 2374delTTTG in the ATP2C1 gene. The 2
families had different alleles of the D3S1587 marker, a locus less
than 100 kb from the mutant gene, on the mutant chromosome. This may
indicate that these were independent mutations. The deletion
resulted in a premature termination codon 10 amino acids downstream
of the mutation. |
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.0005 HAILEY-HAILEY
DISEASE |
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ATP2C1, IVS11, G-A, -1 |
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Sudbrak et al. (2000) identified
a G-to-A transition at the 3-prime end of intron 11 (nucleotide
position 852) of the ATP2C1 gene in a family with Hailey-Hailey
disease (169600).
The effect on the cDNA was not determined. |
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.0006 HAILEY-HAILEY
DISEASE |
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ATP2C1, CYS490PHE |
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In a Japanese patient who represented a sporadic occurrence of
Hailey-Hailey disease (169600), Yokota
et al. (2002) reported
a cys490-to-phe (C490F) amino acid substitution that arose from a
1469G-T transversion in exon 17 of the ATP2C1 gene. |
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.0007 HAILEY-HAILEY
DISEASE |
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ATP2C1, 1-BP DEL, 2460G |
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In a Japanese patient who represented a sporadic occurrence of
Hailey-Hailey disease (169600), Yokota
et al. (2002) reported
a frameshift mutation in the ATP2C1 gene, 2460delG, that resulted in
a premature termination codon at exon 25. |
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.0008 HAILEY-HAILEY
DISEASE |
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ATP2C1, LEU584PRO |
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In a Japanese patient who represented a sporadic occurrence of
Hailey-Hailey disease (169600), Yokota
et al. (2002) reported
a T-to-C transition at nucleotide 1751 in exon 19 of the ATP2C1
gene, resulting in a leu584-to-pro (L584P) amino acid substitution. |
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.0009 HAILEY-HAILEY
DISEASE |
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ATP2C1, IVS22, G-A, +1 |
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In a patient with unilateral segmental exacerbations of
Hailey-Hailey disease (169600),
originally reported by Vakilzadeh
and Kolde (1985), Poblete-Gutierrez
et al. (2004) identified
heterozygosity for a G-to-A transition at the first base of the
consensus splice donor site of exon 22 of the ATP2C1 gene. The
mutation, which they designated 2146+1G-A, resulted in the skipping
of the 69-bp exon 22. 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. |
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REFERENCES |
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1. |
Chao, S.-C., Tsai, Y.-M., Yang, M.-H. Mutation
analysis of ATP2C1 gene in Taiwanese patients with
Hailey-Hailey disease. Brit.
J. Derm. 146: 595-600, 2002. [PubMed: 11966689, related
citations] [Full Text: Blackwell
Publishing, Pubget] |
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2. |
Dobson-Stone, C., Fairclough, R., Dunne, E., Brown, J.,
Dissanayake, M., Munro, C. S., Strachan, T., Burge, S.,
Sudbrak, R., Monaco, A. P., Hovnanian, A. Hailey-Hailey
disease: molecular and clinical characterization of
novel mutations in the ATP2C1 gene. J.
Invest. Derm. 118: 338-343, 2002. [PubMed: 11841554, related
citations] [Full Text: Nature
Publishing Group,Pubget] |
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3. |
Hu, Z., Bonifas, J. M., Beech, J., Bench, G., Shigihara,
T., Ogawa, H., Ikeda, S., Mauro, T., Epstein, E. H., Jr. Mutations
in ATP2C1, encoding a calcium pump, cause Hailey-Hailey
disease. Nature
Genet. 24: 61-65, 2000. [PubMed: 10615129,related
citations] [Full Text: Nature
Publishing Group, Pubget] |
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4. |
Ikeda, S., Shigihara, T., Mayuzumi, N., Yu, X., Ogawa,
H. Mutations
of ATP2C1 in Japanese patients with Hailey-Hailey
disease: intrafamilial and interfamilial phenotype
variations and lack of correlation with mutation
patterns. J.
Invest. Derm. 117: 1654-1656, 2001. [PubMed: 11886536, related
citations] [Full Text: Nature
Publishing Group, Pubget] |
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5. |
Poblete-Gutierrez, P., Wiederholt, T., Konig, A., Jugert,
F. K., Marquardt, Y., Rubben, A., Merk, H. F., Happle,
R., Frank, J.Allelic
loss underlies type 2 segmental Hailey-Hailey disease,
providing molecular confirmation of a novel genetic
concept. J.
Clin. Invest. 114: 1467-1474, 2004. [PubMed: 15545997, related
citations] [Full Text: Journal
of Clinical Investigation,Pubget] |
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6. |
Sudbrak, R., Brown, J., Dobson-Stone, C., Carter, S.,
Ramser, J., White, J., Healy, E., Dissanayake, M.,
Larregue, M., Perrussel, M., Lehrach, H., Munro, C. S.,
Strachan, T., Burge, S., Hovnanian, A., Monaco, A. P. Hailey-Hailey
disease is caused by mutations in ATP2C1 encoding a
novel Ca2+ pump. Hum.
Molec. Genet. 9: 1131-1140, 2000. [PubMed: 10767338, related
citations] [Full Text: HighWire
Press, Pubget] |
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7. |
Vakilzadeh, F., Kolde, G. Relapsing
linear acantholytic dermatosis. Brit.
J. Derm. 112: 349-355, 1985. [PubMed: 3978039,related
citations] [Full Text: Pubget] |
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8. |
Yokota, K., Takizawa, Y., Yasukawa, K., Kimura, K.,
Nishikawa, T., Shimizu, H. Analysis
of ATP2C1 gene mutation in 10 unrelated Japanese
families with Hailey-Hailey disease. J.
Invest. Derm. 118: 550-551, 2002. [PubMed: 11874499, related
citations] [Full Text: Nature
Publishing Group, Pubget] |
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Official Symbol
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ATP2C1provided
by HGNC
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Official Full Name
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ATPase, Ca++ transporting, type 2C, member 1provided
by HGNC
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Primary source
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HGNC:13211
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Locus tag
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HUSSY-28
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See related
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Ensembl:ENSG00000017260; HPRD:05089; MIM:604384
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Gene type
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protein coding
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RefSeq status
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REVIEWED
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Organism
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Homo sapiens
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Lineage
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Eukaryota; Metazoa; Chordata; Craniata; Vertebrata;
Euteleostomi; Mammalia; Eutheria; Euarchontoglires;
Primates; Haplorrhini; Catarrhini; Hominidae; Homo
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Also known as
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HHD; BCPM; PMR1; SPCA1; hSPCA1; ATP2C1A; KIAA1347
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Summary
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The protein encoded by this gene belongs to the family
of P-type cation transport ATPases. This
magnesium-dependent enzyme catalyzes the hydrolysis of
ATP coupled with the transport of calcium ions. Defects
in this gene cause Hailey-Hailey disease, an autosomal
dominant disorder. Alternatively spliced transcript
variants encoding different isoforms have been
identified. [provided by RefSeq, Aug 2011
Location: 3q22.1, Sequence: Chromosome: 3; NC_000003.11
(130569369..130735556)
Chromosome 3 - NC_000003.11
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