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Exon 12 of the ATP2A2 gene in patients with Darier disease: one novel mutation and one previously described

Editor Darier disease (DD; OMIM: 124200), also known as Darier– White disease, keratosis follicularis, is a rare autosomal dominant heritable disease estimated to affect 1/55 000–1/100 000 individuals. It is characterized clinically by warty papules and plaques over the seborrhoeic area, such as central trunk, flexures, scalp and forehead, mostly presenting before the third decade. The disorder may present with various clinical manifestations including the nails, oral mucosa and neuropsychiatric abnormalities. DD is caused by mutations in the ATP2A2 gene (MIM: 108740), which encodes the enzyme sarco/endoplasmic reticulum Ca ATPase type 2 (SERCA2-ATPase), a calcium pump in the sarcoplasmic reticulum that utilizes the chemical energy from ATP. The ATP2A2 mutations have been detected in patients of varying ethnic backgrounds. Here, we describe the identification of two mutations in ATP2A2 gene in two families with DD. Two three-generation families with DD from Chongqing in China were recruited. Family A consisted of two affected and five unaffected individuals, family B consisted of three affected and seven unaffected individuals. The proband of family A, a 51-year-old man, presented with a 39-year history of itchy and hyperkeratotic papules and plaques on the face (Fig. 1a), upper trunk and extremities. These lesions were exacerbated in hot summer or after sun exposure. The index case in pedigree B was a 47-year-old woman who developed similar skin lesions (Fig. 1b) at the age of 15 years. The diagnosis was confirmed by clinical and histopathological findings. The study was approved by Ethical Review Committee of Chongqing hospital of traditional Chinese medicine with written informed consent obtained for every subject. Genomic DNA was extracted using standard procedures from EDTA blood samples. All exons of ATP2A2 gene were amplified by touchdown PCR from genomic DNA. The reaction products purified were sequenced in both directions on an automated DNA sequencer (ABI 3730; Applied Biosystems, Foster City, CA, USA). We identified two heterozygous mutations in exon 12 of the ATP2A2 gene in two different families. A heterozygous A to G transition occurred in nucleotide 1540 in the patients of family A, which results in a lysine to glutamic acid substitution at codon 514 (K514E) (Fig. 2a). A heterozygous C to T transition at nucleotide 1484 (The splice site is indicated by a black vertical bar in Fig. 2) results in a serine to leucine substitution at codon 495 (S495L) (Fig. 2c) in the patients of family B. These two mutations were not detected in unaffected individuals in the two families and the 100 unrelated controls, suggesting that they were not common polymorphisms. The former mutation was novel and the latter has been reported previously. The human ATP2A2 gene, mapped to 12q23–24.1, spans a region of 76 kb, consists of 21 exons, and encodes a 4.5-kb transcript consisting of three cytoplasmic domains and transmembrane helices. ATP2A2 defects may affect the expression level of SERCA2b, disturb cell–cell adhesion and keratinocyte differentiation and signalling. So far, over 232 pathogenic mutations have been detected within ATP2A2 gene in patients with DD, which were scattered along the entire gene without any clustering. The two mutations were located within the phosphorylation region. Intriguingly, the other missense mutations K514R (c.1541 A>G) in the same lysine codon were reported in DD patients associated with neuropsychiatric disorders from Anhui Province in China. K514E is the second mutation found to affect this residue. At amino acid position 495, the S495L muta-