title: Mosaicism in segmental Darier disease: an in-depth molecular analysis quantifying proportions of mutated alleles in various tissues.
abstract: Darier disease is an autosomal dominant genodermatosis caused by germline mutations in the ATP2A2 gene. Clinical expression is variable, including rare segmental phenotypes thought to be caused by postzygotic mosaicism. Genetic counseling of segmental Darier patients is complex, as risk of transmitting a nonsegmental phenotype to offspring is of unknown magnitude. We present the first in-depth molecular analysis of a mosaic patient with segmental disease, quantifying proportions of mutated and normal alleles in various tissues. Pyrosequence analysis of DNA from semen, affected and normal skin, peripheral leukocytes and hair revealed an uneven distribution of the mutated allele, from 14% in semen to 37% in affected skin. We suggest a model for segmental manifestation expression where a threshold number of mutated cells is needed for manifestation development. We further recommend molecular analysis of the ATP2A2 gene in semen of male patients with segmental Darier disease to improve genetic counseling.
authors: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors: Theresa Larriba
authors: TL
authors: Harboe
authors: Patrick
authors: P
authors: Willems
authors: Cathrine
authors: C
authors: Jespersgaard
authors: Marie Louise
authors: ML
authors: Mølgaard Poulsen
authors: Flemming Brandt
authors: FB
authors: Sørensen
authors: Marie Luise
authors: ML
authors: Bisgaard
mesh_terms: D000328:Adult; D007644:Darier Disease / Q000235:genetics*; D005817:Genetic Counseling; D006801:Humans; D007962:Leukocytes; D008297:Male; D009030:Mosaicism; D009154:Mutation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics; D012661:Semen; D012867:Skin
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human