Two novel mutations in the ATP2A2 gene in Chinese patients with Darier disease

ARTICLE

Auteur(s) : Jia Huo, XiaoPeng Wang, YingYing Dong, JiaWen Wu, XiaoLi Li, Yan Liu, SengXiang Xiao

Department of Dermatology, the Second Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, R.P. China

Darier disease (DD; OMIM 124200) is a rare autosomal dominant hereditary skin disorder characterized by warty papules and plaques on the seborrheic areas of the skin. The cause of DD is defects in the ATP2A2 gene on chromosome 12q23-24.1 [1]. This gene encodes the sarco/endoplasmic reticulum Ca²⁺ ATPase isoform 2 (SERCA2), which transports Ca²⁺ from the cytosol into the endoplasmic reticulum lumen and plays a key role in intracellular calcium signaling [1-3]. We report here two novel mutations in a Chinese pedigree and a sporadic case with DD.

The proband in the pedigree (figure 1A) was a 30-year-old male who presented with scattered brown keratotic papules on the neck and face at the age of 28. During the next 2 years, the lesions gradually spread to the trunk, axillae and inguina (figure 1B). However, other patients in this pedigree had shown slight skin-coloured hyperkeratotic papules on the face since their mid-teen years. The sporadic case was a 37-year-old male. He developed symptoms from the age of 7 and presented with malodorous verrucous papules and plaques on the scalp, face and trunk (figure 1C). None of the patients in our study suffered from neuropsychiatric symptoms and the sporadic case had no family history of skin disease. Skin biopsies showed typical features of DD, including orthokeratotic hyperkeratosis, suprabasal acantholysis, corps ronds and grains. The diagnosis of DD was based on clinical and histological findings.

After informed consents were obtained, genomic DNA was extracted from peripheral blood samples. All 21 exons, including intron-exon boundaries, were amplified by polymerase chain reaction (PCR). The primers were designed according to previously published information [4]. The PCR products were directly sequenced using dry terminator chemistry on an ABI PRISMTM 377 DNA sequencer. We identified a deletion mutation (1622delAACA) and a missense mutation (698G>T). The same mutations were not detected in DNA samples of 100 unrelated individuals.

The two mutations we detected are located within the ATP-binding domain and the β-strand domain, respectively. These functional domains have been shown to be highly conserved during evolution, with 97.7% and 100% homology in different species, and may be critical for the function of the protein [1, 4, 5].

The pedigree had a 4bp deletion, 1622delAACA, leading to a PTC 28 codon downstream from the deletion site in exon13 (figure 1D). This mutation predicts the absence of protein synthesis through nonsense mRNA decay. In this pedigree, DD patients have marked clinical heterogeneity. T.Onozuka et al. [6] reported two DD pedigrees with intrafamilial variability and they suggested that mutations located near the Ca²⁺-binding sites might produce clinical heterogeneity. However, in our study, the mutation 1622delAACA is located within the ATP-binding domain which is far from the Ca²⁺-binding sites. This shows that mutations of the ATP2A2 gene located near the Ca²⁺-binding sites might not be a necessary prerequisite for intrafamilial variability of DD and additional factors might produce these clinical differences.

In the sporadic case, we detected a missense mutation 698G>T in exon8, which led to the substitution of glycine by valine at codon 233(G233V) (figure 1E). A previously reported mutation of the same residue to an arginine (G233R) has the similar clinical manifestation of our sporadic case, implying that this residue, which is located in the β-strand domain, plays an important role in SERCA2 function and the replacement causes an alteration in the steric and biochemical properties of the protein [4, 6].

In conclusion, we have reported another two novel mutations in ATP2A2 gene in Chinese patients with DD. This study adds new variants to the knowledge of ATP2A2 mutations and should be useful for genetic counselling and prenatal diagnosis for affected families.

Acknowledgments

References

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