Novel and recurrent variants of ATP2C1 identified in patients with Hailey-Hailey disease (original) (raw)
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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.
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.
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.
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...
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.
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.
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.
Four novel ATP2A2 mutations in Slovenian patients with Darier disease
Journal of the American Academy of Dermatology, 2010
Background: Darier disease (DD) is an autosomal dominant genodermatosis caused by mutations in the ATP2A2 gene. It has been reported that depletion of Ca 21 stores within the endoplasmic reticulum of keratinocytes is associated with impaired cell cycle regulation and terminal differentiation. Mechanical stress, heat, or UV irradiation might delay cell cycle exit and permit progression into the quiescent stage without repair. When there is associated DNA damage, this can lead to an accumulation of secondary somatic mutations and possible clonal proliferation of damaged keratinocyes within keratotic papules and plaques.