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Novel and recurrent variants of ATP2C1 identified in patients with Hailey-Hailey disease.

ABSTRACT: Hailey-Hailey disease (HHD) is a rare, late-onset autosomal dominant genodermatosis characterized by blisters, vesicular lesions, crusted erosions, and erythematous scaly plaques predominantly in intertriginous regions. HHD is caused by ATP2C1 mutations. About 180 distinct mutations have been identified so far; however, data of only few cases from Central Europe are available. The aim was to analyze the ATP2C1 gene in a cohort of Polish HHD patients. A group of 18 patients was enrolled in the study based on specific clinical symptoms. Mutations were detected using Sanger or next generation sequencing. In silico analysis was performed by prediction algorisms and dynamic structural modeling. In two cases, mRNA analysis was performed to confirm aberrant splicing. We detected 13 different mutations, including 8 novel, 2 recurrent (p.Gly850Ter and c.325-3 T?>?G), and 6 sporadic (c.423-1G?>?T, c.899?+?1G?>?A, p.Leu539Pro, p.Thr808TyrfsTer16, p.Gln855Arg and a complex allele: c.[1610C?>?G;1741?+?3A?>?G]). In silico analysis shows that all novel missense variants are pathogenic or likely pathogenic. We confirmed pathogenic status for two novel variants c.325-3 T?>?G and c.[1610C?>?G;1741?+?3A?>?G] by mRNA analysis. Our results broaden the knowledge about genetic heterogeneity in Central European patients with ATP2C1 mutations and also give further evidence that careful and multifactorial evaluation of variant pathogenicity status is essential.

SUBMITTER: Sawicka J

PROVIDER: S-EPMC7148260 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Novel and recurrent variants of ATP2C1 identified in patients with Hailey-Hailey disease.

Sawicka J J Kutkowska-Kaźmierczak A A Woźniak K K Tysarowski A A Osipowicz K K Poznański J J Rygiel A M AM Braun-Walicka N N Niepokój K K Bal J J Kowalewski C C Wertheim-Tysarowska K K

Journal of applied genetics 20200125 2

Hailey-Hailey disease (HHD) is a rare, late-onset autosomal dominant genodermatosis characterized by blisters, vesicular lesions, crusted erosions, and erythematous scaly plaques predominantly in intertriginous regions. HHD is caused by ATP2C1 mutations. About 180 distinct mutations have been identified so far; however, data of only few cases from Central Europe are available. The aim was to analyze the ATP2C1 gene in a cohort of Polish HHD patients. A group of 18 patients was enrolled in the st ...[more]

PMID: 31983024

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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.

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Novel and recurrent variants of ATP2C1 identified in patients with Hailey-Hailey disease.

Publications

Novel and recurrent variants of ATP2C1 identified in patients with Hailey-Hailey disease.

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