New mutations of Darier disease in Tunisian patients

Abstract

Darier's disease (DD, MIM 124200) also known as Darier-White disease and keratosis follicularis, is a rare autosomal dominant skin disorder characterized by warty papules and plaques in the seborrheic area (central trunk, flexures, scalp, and forehead). Pathogenic mutations in the ATP2A2 gene encoding the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (SERCA) 2 gene underlie the disease. In the present study, we performed genetic investigation of three unrelated Tunisian families affected by DD. Mutation screening was performed by direct sequencing of the coding region and exon/intron boundaries of the ATP2A2 gene. Patients in the 3 studied families exhibited classical DD phenotype. DD was associated with neurological and cardiac disorders in one family. Two novel mutations were identified: a missense mutation (R559Q) and a frameshift mutation (1713-1714 del 2A). Both pathogenic mutations are located in exon 13 of the ATP2A2 gene and affected the ATP-binding site of the SERCA2 protein. In one family, no mutation was found within the coding region and exon/intron boundaries of the ATP2A2 gene. Our findings provide further evidence for the genetic heterogeneity of DD in Tunisia and that most mutations involved in this disease are family specific.

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

“…We did not find mutations in 17 patients (24%) with DD and three patients (17%) with HHD, which is similar to figures reported in the literature [Sakuntabhai et al., ; Hu et al., ; Ikeda et al., ; Ringpfeil et al., ; Dobson‐Stone et al., ; Yokota et al., ; Ikeda et al., ; Li et al., ; Zhang et al., ; Hamada et al., ; Bchetnia et al., ; Cheng et al., ; Godic et al., ; Fu et al., ; Klausegger et al., ; Green et al., ; ]. Of interest though, one DD patient showed skipping of exon 4 of ATP2A2 on the mRNA level, which indicates that, for instance, larger deletions or cryptic splice‐site mutations may account for the disease phenotype.…”

“…However, in a patient with a comparable phenotype, no variants in ATP2A2 were found [Lora et al., ]. Patients with a similar frameshift mutation in the adjacent codon 40 (c.119_120delAG, p.(Glu40Valfs * 4)) showed the classical DD phenotype [Ruiz‐Perez et al., ; Bchetnia et al., ].…”

Novel ATP2A2 mutations in a large sample of individuals with Darier disease

“…To date more than 187 pathogenic mutations have been described throughout the gene, including missense, nonsense, substitutions, insertions and deletions both frame‐shift and in‐frame (Miyauchi et al., for all references 2006 and earlier, and subsequent references). These mutations do not seem to cluster within “hot‐spot” regions throughout the primary sequence of the SERCA2b molecule and most are unique within individual families.…”

Identification of mutation c.632G>A (p.G211D) in the ATP2A2 gene and genotype–phenotype correlation in a large Chinese family with Darier’s disease

“…This mutation was previously described in European patients with DD 8 but was not found in reported Chinese patients with DD. None of the other ATP2A2 gene mutations (among the available mutation list that is up to 150) [2][3][4][5][6][7][8][9][10][11] were found in our patient with DD except for c.632G>A (p.G211D). The presence of this mutation was further screened in --II:1 Female 45 No --II:3 Female 41 Yes 5 ++++ II:5 Male 39 Yes 14 ++++ II:8 Female 34 Yes 17 +++ II:9 Female 34 No --II:11 Female 32 No --III:5 Female 17 Yes 15 ++ III:6 Female 16 No --III:7 Female 14 No --III:8 Female 12 Yes 9 +++ III:9 Male 10 Yes 8 + III:10 Male 9 Yes 9 + III:11 Male 5 Yes ?…”

“…2 There are at least 150 ATP2A2 mutations documented in patients with DD at present. [2][3][4][5][6][7][8][9][10][11] However, almost all identified mutations are family specific and are not observed in multiple families. 12 Additionally the relationship between genotype and DD phenotype has not been sufficiently established.…”