A Case of Hailey-Hailey Disease with a Novel Nonsense Mutation in the ATP2C1 Gene (original) (raw)
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Hailey-Hailey Disease: Molecular and Clinical Characterization of Novel Mutations in the ATP2C1 Gene
Journal of Investigative Dermatology, 2002
Hailey±Hailey disease is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. Mutations in ATP2C1, the gene encoding a novel, P-type Ca 2+transport ATPase, were recently found to cause Hailey±Hailey disease. In this study, we used conformation-sensitive gel electrophoresis to screen all 28 translated exons of ATP2C1 in 24 Hailey±Hailey disease families and three sporadic cases with the disorder. We identi®ed 22 different mutations, 18 of which have not previously been reported, in 25 probands. The novel mutations comprise three nonsense, six insertion/deletion, three splice-site, and six missense mutations and are distributed throughout the ATP2C1 gene. Six mutations were found in 0022-202X/02/$15.00´Copyright #
A novel mutation in the ATP2C1 gene is associated with Hailey-Hailey disease in a Chinese family
International Journal of Dermatology, 2009
Background A three-generation Chinese family with Hailey-Hailey disease (HHD) was identified and characterized. The proband developed HHD with severe recurrent blisters and crusted erosions involving the body folds. Skin biopsy studies showed epidermal hyperkeratosis and defects in cell-to-cell adhesion. Three other members in the family were also affected with HHD and had the same clinical manifestations. The purpose of this study was to identify the pathogenic gene or mutation in the family. Methods All exons and exon-intron boundaries of ATP2C1 were polymerase chain reaction (PCR) amplified and sequenced with DNA samples from the proband. Restriction fragment length polymorphism (RFLP) analysis for the intron 23-exon 24 boundary of ATP2C1 was performed in all family members and in 100 normal control subjects.
ATP2C1 Gene Mutation Analysis in Italian Patients with Hailey–Hailey Disease
Journal of Investigative Dermatology, 2005
Hailey-Hailey disease (HHD) is a rare autosomal dominant disorder characterized by recurrent skin lesions predominantly involving the body folds. It is caused by heterozygous mutations in the ATP2C1 gene, encoding the human secretory pathway Ca 2 þ /Mn 2 þ -ATPase protein 1 (hSPCA1). In this report we describe the molecular studies performed in eight HHD cases from Italy that led us to identify six different mutations scattered through the ATP2C1 gene in seven of eight cases. Four of the detected mutations were novel. Our results confirm the high allelic heterogeneity of the ATP2C1 gene and support the notion that HHD is a genetically homogeneous disorder. Furthermore, we created a table summarizing all previously reported ATP2C1 mutations, adapting the nomenclature, if needed, according to the guidelines of the Human Genome Variation Society.
A Family with Atypical Hailey Hailey Disease- Is There More to the Underlying Genetics than ATP2C1?
PloS one, 2015
The autosomal dominant Hailey Hailey disease (HHD) is caused by mutations in the ATP2C1 gene encoding for human secretory pathway Ca2+/Mn2+ ATPase protein (hSPCA1) in the Golgi apparatus. Clinically, HHD presents with erosions and hyperkeratosis predominantly in the intertrigines. Here we report an exome next generation sequencing (NGS) based analysis of ATPase genes in a Greek family with 3 HHD patients presenting with clinically atypical lesions mainly localized on the neck and shoulders. By NGS of one HHD-patient and in silico SNP calling and SNP filtering we identified a SNP in the expected ATP2C1 gene and SNPs in further ATPase genes. Verification in all 3 affected family members revealed a heterozygous frameshift deletion at position 2355_2358 in exon 24 of ATP2C1 in all three patients. 7 additional SNPs in 4 ATPase genes (ATP9B, ATP11A, ATP2B3 and ATP13A5) were identified. The SNPs rs138177421 in the ATP9B gene and rs2280268 in the ATP13A5 gene were detected in all 3 affected...
A novel nonsense ATP2C1 mutation causes Hailey-Hailey disease in a Tunisian family
Our Dermatology Online
Background: Hailey-Hailey disease (HHD) is an autosomal dominant blistering skin disorder that manifests in the third to fourth decade of life. The ATP2C1 has been identified as the pathogenic gene of this disease since 2000. Materials and Methods: We report here a three generations Tunisian pedigree, where almost all males are severely affected and present with complete penetrance of HHD, while only one female shows a mild disease's phenotype in her fourth decade. A molecular study using Whole exome sequencing and direct sequencing was performed to this family. Results: By whole exome sequencing and direct DNA sequencing, a novel nonsense mutation in ATP2C1 (c.2698A>T; p.Lys900Ter) was identified in all patients, supporting that alterations in ATP2C1 are causative of HHD. Unexpectedly, this mutation was found in one female who was initially not diagnosed for HHD. Our observations would be in line with incomplete penetrance and variable expressivity between male and female of this disease, or evidence for genetic modifiers. Conclusion: We report here a novel nonsense heterozygous mutation in ATP2C1 gene in 5 patients with HHD. Interestingly, one woman carries the nonsense ATP2C1 mutation but displays a mild phenotype of HHD. This could indicate a variation in pattern and expressivity between male and female developing HHD phenotype which should be considered when providing genetic counselling to family members carrying such mutations.
Novel and recurrent variants of ATP2C1 identified in patients with Hailey-Hailey disease
Journal of Applied Genetics, 2020
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.[1...
Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca2+ pump
Human Molecular Genetics, 2000
genetic linkage studies localized the gene to a 5 cM interval on human chromosome 3q21. After reducing the disease critical region to <1 cM, we used a positional cloning strategy to identify the gene ATP2C1, which is mutated in HHD. ATP2C1 encodes a new class of P-type Ca 2+ -transport ATPase, which is the homologue for the rat SPLA and the yeast PMR1 medial Golgi Ca 2+ pumps and is related to the sarco(endo)plasmic calcium ATPase (SERCA) and plasma membrane calcium ATPase (PCMA) families of Ca 2+ pumps. The predicted protein has the same apparent transmembrane organization and contains all of the conserved domains present in other P-type ATPases. ATP2C1 produces two alternative splice variants of ∼4.5 kb encoding predicted proteins of 903 and 923 amino acids. We identified 13 different mutations, including nonsense, frameshift insertion and deletions, splice-site mutations, and nonconservative missense mutations. This study demonstrates that defects in ATP2C1 cause HHD and together with the recent identification of ATP2A2 as the defective gene in Darier's disease, provide further evidence of the critical role of Ca 2+ signaling in maintaining epidermal integrity.
PLOS ONE, 2015
Hailey-Hailey disease (HHD) is an inherited blistering dermatosis characterized by recurrent erosions and erythematous plaques that generally manifest in intertriginous areas. Genetically, HHD is an autosomal dominant disease, resulting from heterozygous mutations in ATP2C1, which encodes a Ca 2+ /Mn 2+ ATPase. In this study, we aimed at identifying and analyzing mutations in five patients from unrelated families diagnosed with HHD and study the underlying molecular pathogenesis.
Cell Death & Disease, 2016
ATP2C1gene codes for the secretory pathway Ca2+/Mn2+-ATPase pump type 1 (SPCA1) localizing at the golgi apparatus. Mutations on the humanATP2C1gene, causing decreased levels of the SPCA1 expression, have been identified as the cause of the Hailey–Hailey disease, a rare skin disorder. In the last few years, several mutations have been described, and here we summarize how they are distributed along the gene and how missense mutations affect protein expression. SPCA1 is expressed in four different isoforms through alternative splicing of theATP2C1gene and none of these isoforms is differentially affected by any of these mutations. However, a better understanding of the tissue specific expression of the isoforms, their localization along the secretory pathway, their specific binding partners and the role of the C-terminal tail making isoforms different from each other, will be future goals of the research in this field.
Journal of Biological Chemistry, 2003
ATP2C1, encoding the human secretory pathway Ca 2؉ /Mn 2؉ ATPase (hSPCA1), was recently identified as the defective gene in Hailey-Hailey Disease (HHD), an autosomal dominant skin disorder characterized by persistent blisters and erosions. To investigate the underlying cause of HHD, we have analyzed the changes in expression level and function of hSPCA1 caused by mutations found in HHD patients. Mutations were introduced into hSPCA1d, a novel splice variant expressed in keratinocytes, described here for the first time. Encoded by the full-length of optional exons 27 and 28, hSPCA1d was longer than previously identified splice variants. The protein competitively transported Ca 2؉ and Mn 2؉ with equally high affinity into the Golgi of COS-1 cells. Ca 2؉-and Mn 2؉-dependent phosphoenzyme intermediate formation in forward (ATP-fuelled) and reverse (P ifuelled) directions was also demonstrated. HHD mutant proteins L341P, C344Y, C411R, T570I, and G789R showed low levels of expression, despite normal levels of mRNA and correct targeting to the Golgi, suggesting instability or abnormal folding of the mutated hSPCA1 polypeptides. P201L had little effect on the enzymatic cycle, whereas I580V caused a block in the E 1 ϳP 3 E 2-P conformational transition. D742Y and G309C were devoid of Ca 2؉-and Mn 2؉-dependent phosphoenzyme formation from ATP. The capacity to phosphorylate from P i was retained in these mutants but with a loss of sensitivity to both Ca 2؉ and Mn 2؉ in D742Y and a preferential loss of sensitivity to Mn 2؉ in G309C. These results highlight the crucial role played by Asp-742 in the architecture of the hSPCA1 ion-binding site and reveal a role for Gly-309 in Mn 2؉ transport selectivity. At present, three distinct classes of phosphorylation-type Ca 2ϩ transport ATPases have been identified in mammalian * This work was supported in part by the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.