Recurrent p.N767S mutation in the ATP2A2 gene in a Japanese family with haemorrhagic Darier disease clinically mimicking epidermolysis bullosa simplex with mottled pigmentation

Abstract

Darier disease (DD; MIM 124200) is an autosomal dominant disorder that usually presents in teenagers or adults with multiple keratotic papules or plaques in seborrhoeic areas, although considerable clinical diversity may exist. 1 Nevertheless, skin biopsy typically shows suprabasal acantholysis of the epidermis with overlying dyskeratotic cells, and transmission electron microscopy reveals loss of desmosomal attachments and perinuclear aggregates of keratin intermediate filaments. 2 Moreover, all cases of DD, whatever the nature of the clinicopathological manifestations, appear to be due to heterozygous mutations in the ATP2A2 gene. 3,4 One unusual clinical presentation is the acral haemorrhagic variant, haemorrhagic DD (HDD), 5 which has been rarely reported. [6][7][8] In this report, we describe a Japanese family with HDD. This pedigree is of interest because of the difficulties in making a clinical diagnosis and also the nature of the underlying ATP2A2 mutation which has implications for genotype-phenotype correlation in this genodermatosis.

Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey-Hailey Disease

“…(Asp702Asn) reported five times, and c.2249G>A/p. (Arg750Glu) reported four times [Jacobsen et al., ; Ruiz‐Perez et al., ; Sakuntabhai et al., , ; Mac Manus et al., ; Ringpfeil et al., ; Chao et al., ; Ikeda et al., ; Onozuka et al., ; Racz et al., ; Hamada et al., ; Bchetnia et al., ; Godic et al., ; Fu et al., ; Pedace et al., ; Green et al., ; Li et al., ; Shi et al., ; Dodiuk‐Gad et al., ]. At amino acid positions 131 and 495, other base substitutions c.392G>T/p.…”

“…It is interesting to note that the most prevalent recurrent mutations in ATP2A2 are base substitutions resulting in missense mutations: c. [Jacobsen et al, 1999;Ruiz-Perez et al, 1999;Sakuntabhai et al, 1999aSakuntabhai et al, , 1999bMac Manus et al, 2001;Ringpfeil et al, 2001;Chao et al, 2002;Ikeda et al, 2003;Onozuka et al, 2004;Racz et al, 2005;Hamada et al, 2007;Bchetnia et al, 2009b;Godic et al, 2010a;Fu et al, 2011;Pedace et al, 2011;Green et al, 2013;Li et al, 2014;Shi et al, 2015;Dodiuk-Gad et al, 2016]. At amino acid positions 131 and 495, other base substitutions c.392G>T/p.…”

“…The low prevalence of the other clinical subtypes of DD (acralhemorrhagic and comedonal DD) makes defining a genotypephenotype correlation even more difficult. Two studies identified the p.(Asn767Ser) missense mutation in four unrelated patients with acral-hemorrhagic DD [Ruiz-Perez et al, 1999;Hamada et al, 2007]. However, other DD patients with the p.(Asn767Ser) mutation did not suffer from acral-hemorrhagic blistering [Jacobsen et al, 1999;Fu et al, 2011;Pedace et al, 2011;Green et al, 2013], arguing against this particular genotype-phenotype correlation in DD.…”

A new c.2541delC mutation in the ATP2A2 gene in a Japanese patient with Darier's disease

“…2 Moreover, covered parts of the skin and buccal mucosal can be involved. 3 In our case, the linear lesion follows the lines of Blaschko. Other skin diseases such as congenital, nevoid, and acquired skin diseases may follow Blaschko's lines which are thought to reflect T-lymphocyte migration and clonal expansion during embryogenesis.…”

“…The evidence for the specific ATP2A2 gene mutation p.Asn767Ser in the acral haemorrhagic variant of DD has been reported in four unrelated European families and one Japanese family, establishing this particular amino acid substitution as the most common mutation in the acral haemorrhagic DD. 2,3 However, no paradigm for any other genotype-phenotype correlations has emerged. It is plausible that modifying genes and/or environmental factors might influence inter-and intrafamilial phenotypic variations in DD.…”