PMID- 10441323
OWN - NLM
STAT- MEDLINE
DCOM- 20000127
LR  - 20191210
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 9
DP  - 1999 Sep
TI  - Spectrum of novel ATP2A2 mutations in patients with Darier's disease.
PG  - 1611-9
AB  - Darier's disease (DD) is an autosomal dominantly inherited skin disorder
      characterized by loss of adhesion between epidermal cells (acantholysis) and
      abnormal keratinization. Recently, we identified ATP2A2 encoding the
      sarco/endoplasmic reticulum Ca(2+)ATPase isoform 2 as the defective gene in DD.
      Now we report a spectrum of ATP2A2 mutations in 19 families and six sporadic
      cases with DD and investigate genotype-phenotype correlations. All 21 exons and
      flanking intron boundaries were amplified and screened for mutations by
      conformation-sensitive gel electrophoresis and direct sequencing. We identified
      24 novel mutations that are scattered throughout the ATP2A2 gene. Two families
      shared an identical mutation on a common disease-associated haplotype, suggesting
      inheritance from a common ancestor. The majority of the mutations (54%; 13/24)
      led to a premature termination codon which further supports the proposal that
      haploin-sufficiency is a common molecular mechanism for DD. Thirty-eight per cent
      of mutations (9/24) result in non-conservative amino acid substitutions at highly
      conserved positions. Two mutations predict mutated polypeptides lacking or
      carrying additional amino acids. Marked inter- and intrafamilial phenotypic
      variability of the disease was observed. These results illustrate the
      considerable diversity of ATP2A2 mutations causing DD and suggest that additional
      factors are important contributors to the clinical phenotype.
FAU - Sakuntabhai, A
AU  - Sakuntabhai A
AD  - The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt
      Drive, Headington, Oxford OX3 7BN, UK.
FAU - Burge, S
AU  - Burge S
FAU - Monk, S
AU  - Monk S
FAU - Hovnanian, A
AU  - Hovnanian A
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Isoenzymes)
RN  - EC 7.2.2.10 (Calcium-Transporting ATPases)
SB  - IM
MH  - Calcium-Transporting ATPases/*genetics
MH  - DNA Mutational Analysis
MH  - Darier Disease/enzymology/*genetics/pathology
MH  - Europe
MH  - Genotype
MH  - Haplotypes
MH  - Humans
MH  - Isoenzymes/genetics
MH  - *Mutation
MH  - Phenotype
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Skin/pathology
EDAT- 1999/08/11 00:00
MHDA- 1999/08/11 00:01
CRDT- 1999/08/11 00:00
PHST- 1999/08/11 00:00 [pubmed]
PHST- 1999/08/11 00:01 [medline]
PHST- 1999/08/11 00:00 [entrez]
AID - ddc201 [pii]
AID - 10.1093/hmg/8.9.1611 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Sep;8(9):1611-9. doi: 10.1093/hmg/8.9.1611.