Two novel ATP2C1 mutations in patients with Hailey-Hailey disease and a literature review of sequence variants reported in the Chinese population.

Hailey-Hailey disease (HHD) is an autosomal dominant disorder in which the ATP2C1 gene has been implicated. Many mutations of this gene have been detected in HHD patients. To analyze such mutations in HHD and summarize all those identified in Chinese patients with this disease, we examined four familial and two sporadic cases and searched for case reports and papers by using the Chinese Biological Medicine Database and PubMed. HHD diagnoses were made based on clinical features and histopathological findings. Polymerase chain reaction and direct sequencing of the ATP2C1 gene were performed using blood samples from HHD patients, unaffected family members, and 120 healthy individuals. Three mutations were identified, including the recurrent mutation c.2126C>T (p.Thr709Met), and two novel missense mutations, c.2235_2236insC (p.Pro745fs*756) and c.689G>A (p.Gly230Asp). Considering our data, 81 different mutations have now been reported in Chinese patients with HHD. In cases of misannotation or duplication, previously published mutations were renamed according to a complementary DNA reference sequence. These mutations are scattered throughout the ATP2C1 gene, with no evident hotspots or clustering. It is of note that some reported "novel" mutations were in fact found to be recurrent. Our findings expand the range of known ATP2C1 sequence variants in this disease.

Heterogeneous mutations of the ATP2C1 gene causing Hailey-Hailey disease in Hong Kong Chinese.

BACKGROUND: Hailey-Hailey disease (HHD) is a rare autosomal dominant dermatosis. It causes suprabasilar acantholysis leading to vesicular and crusted erosions affecting the flexures. Mutation of ATP2C1 gene encoding the human secretory pathway Ca(2+) /Mn(2+) -ATPase (hSPCA1) was identified to be the cause of this entity. OBJECTIVE: The aim of this study was to study the mutational profile of the ATP2C1 gene in Hong Kong Chinese patients with HHD. METHODS: Patients with the clinical diagnosis of HHD proven by skin biopsy were included in this study. Mutation analysis was performed in 17 Hong Kong Chinese patients with HHD. RESULTS: Ten mutations in the ATP2C1 gene were found. Six of these were novel mutations. The novel mutations included a donor splice site mutation (IVS22+1G>A); a missense mutation (c.1049A>T); two deletion mutations (c.185_188delAGTT and c.923_925delAAG); an acceptor splice site mutation (IVS21-1G>C) and an insertion mutation (c.2454dupT). CONCLUSION: The six novel mutations provide additions to the HHD mutation database. No hot-spot mutation was found and high allelic heterogeneity was demonstrated in the Hong Kong Chinese patients.

Two novel mutations of the ATP2C1 gene in Chinese patients with Hailey-Hailey disease.

Hailey-Hailey disease (HHD; OMIM 169600) is an autosomal dominant blistering disease. Pathogenic mutations in ATP2C1 encoding the human secretory pathway Ca(2+)/Mn(2+)-ATPase protein 1 (hSPCA1) have been identified since 2000. The aim of this study was to report a Chinese pedigree and a sporadic case of HHD and to explore the genetic mutations. The Chinese pedigree and the sporadic case of typical HHD were subjected to mutation detection of ATP2C1. The 27 coding exons and their flanking sequences were amplified and sequenced. The heterozygous C to T transition at nucleotide 2753 in exon 26 and G to T transition at nucleotide 2090 in exon 21 of the ATP2C1 gene were identified in a pedigree and a sporadic case of HHD, respectively. The C2753T transition resulted in a novel nonsense mutation of glutamine codon (CAG) to a stop codon (TAG) at amino acid residue 865 (Q865X) and the G2090T transition resulted in a novel missense mutation of glycine condon (GGA) to Valine (GUA) at amino acid residue 645 (G645V) in hSPCA1. This study should be useful for genetic counseling and prenatal diagnosis for affected families and in expanding the repertoire of ATP2C1 mutations underlying HHD.