title: Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease.
abstract: Acrokeratosis verruciformis of Hopf is a localized disorder of keratinization affecting the distal extremities. Onset is early in life and the disease is inherited in an autosomal dominant fashion. Although histology of acrokeratosis verruciformis lesions shows no evidence of dyskeratosis, a possible relationship with Darier's disease has long been postulated on the basis of clinical similarity. ATP2A2 encoding the sarco(endo)plasmic reticulum Ca2+ ATPase2 pump has been identified as the defective gene in Darier's disease. In this report, we studied a family affected with acrokeratosis verruciformis in six generations and identified a heterozygous P602L mutation in ATP2A2. This mutation predicts a nonconservative amino acid substitution in the ATP binding domain of the molecule. The mutation segregates with the disease phenotype in the family and was not found in 50 controls. Moreover, functional analysis of the P602L mutant showed that it has lost its ability to transport Ca2+. This result demonstrates loss of function of the sarco(endo)plasmic reticulum Ca2+ ATPase2 mutant in acrokeratosis verruciformis, thus providing evidence that acrokeratosis verruciformis and Darier's disease are allelic disorders.
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Jittima
authors.initials: J
authors.lastname: Dhitavat
authors.forename: Sarah
authors.initials: S
authors.lastname: Macfarlane
authors.forename: Leonard
authors.initials: L
authors.lastname: Dode
authors.forename: Natalie
authors.initials: N
authors.lastname: Leslie
authors.forename: Anavaj
authors.initials: A
authors.lastname: Sakuntabhai
authors.forename: Ruth
authors.initials: R
authors.lastname: MacSween
authors.forename: Eric
authors.initials: E
authors.lastname: Saihan
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
mesh_terms: D000293:Adolescent; D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D007644:Darier Disease / Q000235:genetics*; D005192:Family Health; D006801:Humans; D007930:Leucine / Q000235:genetics; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D011392:Proline / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D011392:Proline; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D000252:Calcium-Transporting ATPases; D007930:Leucine; D002118:Calcium