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. Keywords Hailey-Hailey disease. ATP2C1. Genodermatosis The data that support the findings of this study are available from the corresponding author upon reasonable request.

Two novel mutations in the ATP2C1 gene found in Japanese patients with Hailey–Hailey disease

“…Direct nucleotide sequencing of genomic DNA revealed a heterozygous duplication mutation, c.519dup in exon 7, causing a frameshift with PTC at residue 4 downstream in exon 7 (p.R174Tfs*4, Figure 2c). This mutation was the same as those previously reported in HHD diseases 5,10,11 …”

“…Patient 3 had the same mutation in exon 7 (c.519dup, p.R174Tfs*4) as those previously reported in HHD diseases, causing a PTC in exon 7 (A domain) 5,10,11 . Dobson‐Stone et al .…”

“…Sawicka et al . reported a Polish case with familial HHD showing the same mutation; however, precise clinical data are not available 11 . The reported cases with mutation c.519dup, including our case, indicate the interfamilial and intrafamilial variation.…”

Hailey–Hailey disease with a novel variant, c.1978dupG, in the ATP2C1 gene

“…Although over 200 mutations in this gene have been reported to date, 3 no reports have clarified the correlations between the site and type of gene mutation and differences in clinical symptoms 4 . It is also unclear why the clinical symptoms of HHD are solely isolated to the skin, despite ATP2C1 being expressed in all tissues 5 . Accumulation of gene mutations and clinical reports will facilitate further elucidation of disease pathogenesis and the development of more effective treatments for HHD.…”

“…4 It is also unclear why the clinical symptoms of HHD are solely isolated to the skin, despite ATP2C1 being expressed in all tissues. 5 Accumulation of gene mutations and clinical reports will facilitate further elucidation of disease pathogenesis and the development of more effective treatments for HHD. doi: 10.1111/ced.14317 Netherton syndrome (NS), also known as ichthyosis linearis circumflexa, is a rare autosomal recessive disorder.…”