Dataset Information

Identification of 2 Novel Mutations in ATP2C1 Gene in Hailey-Hailey Disease and a Literature Review of Variations in a Chinese Han Population.

ABSTRACT: BACKGROUND Hailey-Hailey disease (HHD) is a rare autosomal dominant skin condition. The ATP2C1 gene was identified as the defective gene in HHD. To date, 166 pathogenic mutations in ATP2C1 have been observed worldwide. The aim of this study was to identify variations in HHD and summarize the features of the mutations identified in China. MATERIAL AND METHODS We examined 2 familial and 2 sporadic cases of HHD. Genomic DNA polymerase chain reaction and direct sequencing of the ATP2C1 were performed from HHD patients, unaffected family members, and 200 healthy individuals. We also searched the published literature for data about the ATP2C1 gene using PubMed and the Chinese Biological Medicine Database. RESULTS We detected 3 heterozygous mutations, including 2 novel frameshift mutations (c.819insA (273LfsX) and c.1264insTAGATGG (421LfsX)) and 1 recurrent nonsense mutation (c.115C>T (R39X)). To the best of our knowledge, 90 different mutations (including our current results) have been reported in China, all of which occurred in the Chinese Han population. CONCLUSIONS Our data may add to the existing list of ATP2C1 mutations and provide new insight into genetic variants of HHD in China.

SUBMITTER: Xu K

PROVIDER: S-EPMC5687790 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Identification of 2 Novel Mutations in ATP2C1 Gene in Hailey-Hailey Disease and a Literature Review of Variations in a Chinese Han Population.

Xu Kejia K Shi Bingjun B Diao Qingchun Q Jiang Xue X Xiao Yujuan Y

Medical science monitor basic research 20171106

BACKGROUND Hailey-Hailey disease (HHD) is a rare autosomal dominant skin condition. The ATP2C1 gene was identified as the defective gene in HHD. To date, 166 pathogenic mutations in ATP2C1 have been observed worldwide. The aim of this study was to identify variations in HHD and summarize the features of the mutations identified in China. MATERIAL AND METHODS We examined 2 familial and 2 sporadic cases of HHD. Genomic DNA polymerase chain reaction and direct sequencing of the ATP2C1 were performe ...[more]

PMID: 29104283

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Project description:BackgroundHailey-Hailey disease (HHD) is an autosomal dominant cutaneous disorder that manifests as repeated blisters and erosions on flexural or intertriginous skin areas. The calcium-transporting ATPase type 2C member 1 gene (ATP2C1) encodes the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1), whose deficiency is responsible for HHD. An ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was previously identified in a Han Chinese family with HHD.MethodsIn this study, the identified ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was investigated in transfected human embryonic kidney 293 cells to analyze its pathogenic mechanism in HHD patients by using cycloheximide chase assay, CCK8 assay and in silico modeling of SPCA1 mutant.ResultsCycloheximide chase assay showed that the degradation rate of the SPCA1 mutant was not obviously faster than that of the normal SPCA1. CCK8 assay showed that cell proliferation rates in the wild-type, A109_Q120del, and empty vector control groups all decreased in the gradient Mn2+ solutions in a dose-dependent manner. The cell proliferation rate in the wild-type was lower than that in the A109_Q120del and empty vector control (both P < 0.01), indicating overexpression of normal SPCA1 may rather induce Golgi stress, and even cell death. The cell proliferation rate in the A109_Q120del was lower than that in the empty vector control (P < 0.01), indicating that overexpression of the mutated SPCA1 may decrease its detoxification capability. Three-dimensional (3D) structure model of SPCA1 built by SWISS-MODEL and PyMOL showed that absence of the 12 amino acids from p.Ala109 to p.Gln120 in the SPCA1 mutant can cause obviously shortened transmembrane 2, which may affect correct localization of SPCA1 on the Golgi.ConclusionThese results demonstrate that the ATP2C1 mutation (c.325-2A>G, p.Ala109_Gln120del) may cause impaired SPCA1 capability to detoxify Mn2+ and abnormal SPCA1 structure, which reveals a new side for the pathogenesis of HHD.

Project description:PurposeTo test for the potential presence of novel mutations in the zinc finger protein (ZNF469) gene in patients with sporadic keratoconus (KC) from a Han Chinese population.MethodsFifty-three patients with primary KC, 30 patients with high myopia (HM), and 100 unrelated population-matched healthy controls without any ocular or systemic disorders, all of Han Chinese ethnicity, were recruited. Blood samples were donated, and genomic DNA was isolated from peripheral blood leukocytes. Sequence variations in ZNF469 were initially identified in patients with KC with next-generation sequencing and subsequently confirmed using Sanger sequencing. Sequence variants identified in patients with KC were subsequently screened in 30 patients with HM and 100 healthy control subjects. Other genes that were reported to be related to KC were also screened in the patients with KC who carried the mutations in ZNF469. The Sorting Intolerant Form Tolerant (SIFT) program was used to predict the effect of amino acid substitution on the ZNF469 protein.ResultsSixteen sequence variants in the coding regions of ZNF469 were identified in this Chinese KC cohort. After five known single nucleotide polymorphisms (SNPs), one false-positive result, and three mutations that were also detected in the results of the whole-exome sequencing (WES) data performed in 220 Han Chinese individuals without ocular abnormalities were removed, seven novel mutations in ZNF469 (c.2059G>A, c.2137C>A, c.3466G>A, c.3749C>T, c.4300G>A, c.4684G>A, and c.7262G>A) that were predicted to be potentially damaging were identified. The patient with KC with the c.3466G>A mutation was also shown to carry one dedicator of cytokinesis 9 (DOCK9) mutation (c.1940C>T). None of the mutations were detected in the patients with HM or the healthy controls. All of the seven mutations in the patients with KC were heterozygote.ConclusionsThe results suggested for the first time that ZNF469 has a pathogenic role in Chinese patients with KC and have widened the mutation spectrum of KC in the Han Chinese population.

Dataset Information

Identification of 2 Novel Mutations in ATP2C1 Gene in Hailey-Hailey Disease and a Literature Review of Variations in a Chinese Han Population.

Publications

Identification of 2 Novel Mutations in ATP2C1 Gene in Hailey-Hailey Disease and a Literature Review of Variations in a Chinese Han Population.

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