Mutations In ATP2C1 Gene Research Articles

Successful Treatment of Refractory Hailey-Hailey Disease with Dupilumab: A Case Report

Hailey-Hailey disease (HHD) is an autosomal dominant blistering dermatosis with incomplete penetrance caused by an ATP2C1 gene mutation. Currently, there is no cure for HHD; however therapeutic options aim to minimize the exacerbating factors and manage patients’ symptoms. A 58-year-old male presented with a 10-year history of biopsy-proven HHD. He was seen consistently over the course of nine years with multiple flares a year consisting of pruritic and painful intertriginous plaques with involvement of the chest, upper arms, and back. His disease was recalcitrant to topicals, oral and topical antibiotics, phototherapy, and systemic corticosteroids. He was started on dupilumab and noticed significant improvement. We present a case of HHD recalcitrant to various modalities of treatment. Our description of rapid improvement with dupilumab suggests a role for Th2 signaling in the pathophysiology of HHD. We propose that dupilumab works for HHD due to the significant skin barrier dysfunction, similar to atopic dermatitis, and consider whether inflammation plays an earlier role in the disease. Although used for an off-label purpose, in this case, further studies should assess the clinical response and safety of patients with recalcitrant HHD treated with dupilumab.

Two Novel ATP2C1 Mutations in Portuguese Patients with Hailey-Hailey Disease


 
 
 Hailey-Hailey disease (HHD) is a rare autosomal dominant acantholytic dermatosis. It is characterized by a recurrent eruption of vesicles, erosions, and scaly erythematous plaques involving intertriginous areas and first occurring after puberty, mostly in the third or fourth decade. In 2000, mutations in the ATP2C1 gene on band 3q22.1, encoding the secretory pathway Ca2+/Mn2+-ATPase protein 1(hSPCA1), have been identified as the cause of HHD. We report the identification of two novel mutations of ATP2C1 gene in two Portuguese patients, which expands the spectrum of ATP2C1 mutations underlying HHD and provides useful information for genetic counseling.
 
 

A novel splice-site mutation in the ATP2C1 gene of a Chinese family with Hailey-Hailey disease.

Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is an autosomal dominant genodermatosis. It is characterized by erosions, blisters and erythematous plaques at sites of friction or intertriginous areas. The pathogenic gene of HHD has been revealed as the ATPase secretory pathway Ca2+ transporting 1 gene ( ATP2C1), which encodes the protein, secretory pathway Ca 2+/Mn 2+-ATPase 1 (SPCA1). ATP2C1 gene mutations are responsible for HHD by resulting in abnormal Ca 2+ homeostasis in the skin and giving rise to acantholysis, a characteristic pathology of HHD. In this study, a four-generation family containing three HHD sufferers was recruited. Direct sequencing of the ATP2C1 gene was performed in the proband and other available family members. Reverse-transcriptase polymerase chain reaction analysis was conducted to show the potential variant effect on ATP2C1 splicing. A novel heterozygous c.325-2A>G transition at the splice acceptor site of intron 4 in the ATP2C1 gene was identified, and it co-segregated with the disease in this family. The mutation resulted in exon 5 skipping and an in-frame deletion of 12 amino acids (p.Ala109_Gln120del) in SPCA1. This splice-site mutation may be responsible for HHD in this family. This study would further expand the mutation spectrum of the ATP2C1 gene and may be helpful in the genetic counseling and prenatal diagnosis of HHD.

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

BackgroundHailey-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/MethodsWe 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.ResultsWe 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.ConclusionsOur data may add to the existing list of ATP2C1 mutations and provide new insight into genetic variants of HHD in China.

The role of the ATP2C1 gene in Hailey-Hailey disease.

Hailey-Hailey disease (HHD) is a rare autosomal dominant acantholytic dermatosis, characterized by a chronic course of repeated and exacerbated skin lesions in friction regions. The pathogenic gene of HHD was reported to be the ATPase calcium-transporting type 2C member 1 gene (ATP2C1) located on chromosome 3q21-q24. Its function is to maintain normal intracellular concentrations of Ca2+/Mn2+ by transporting Ca2+/Mn2+ into the Golgi apparatus. ATP2C1 gene mutations are reportedly responsible for abnormal cytosolic Ca2+/Mn2+ levels and the clinical manifestations of HHD. Environmental factors and genetic modifiers may also affect the clinical variability of HHD. This article aims to critically discuss the clinical and pathological features of HHD, differential diagnoses, and genetic and functional studies of the ATP2C1 gene in HHD. Further understanding the role of the ATP2C1 gene in the pathogenesis of HHD by genetic, molecular, and animal studies may contribute to a better clinical diagnosis and provide new strategies for the treatment and prevention of HHD.

Expression of protein components desmosomal apparatus and cytoskeleton of the epidermis in disease Hailey-Hailey

Hailey-Hailey disease (benign familial chronic pemphigus Guzhero-Hailey-Hailey) - hereditary vesiculo-bullous dermatosis, where mutation of ATP2C1 gene results in morphological changes, which cause an abnormal location of molecules in intercellular adhesion. It is believed that the pathology may involve both the inner surface of the plasma membrane proteins of keratinocytes and desmosomal and adhesion molecules in epidermal intercellular connections. This present research provides the results of immunohistochemical study on the distribution of desmosomal cadherin (desmogleins 1, 2, 3), desmosomal proteins (plakoglobin, desmoplakin I, periplakin), intercellular junctions molecules (E-cadherin, cadherin complex) in desmosomal apparatus and cytoskeletal proteins (cytokeratins 5, 14, suprabasal layers of epidermis) in clinically intact and affected skin of patients with Hailey-Hailey disease. The research also detected violation in localization of the protein components in the system of intercellular junctions and the cytoskeleton from severe immunohistochemical reaction to disappearance and appearance in places not typical for its localization. Thus, the most severe expression of protein molecules was observed in the areas of acantholysis and the formation of intra-epidermal blisters with the penetration of specific material into the cytoplasm of keratinocytes and some acantholytic cells. Besides, in the clinically intact skin areas of patients the most intense damage (almost complete absence of expression or its “masking”) was identified as a damage with the cadherin adhesion molecules. The paradoxical phenomenon - intranuclear and/or perinuclear luminescence was marked by cytokeratin 5, desmogleins and cadherins. The complex mechanism of Hailey-Hailey disease involving various adhesion molecules and protein components of intercellular connections system requires ongoing detailed study of the expression of multiple adhesion molecules associated with the system of intercellular junctions. The acquired knowledge will bring understanding of the sequence of events in pathology (acantholysis) development and the identification of a number of additional differential diagnostic signs of Hailey-Hailey disease.

ATP2C1 gene mutations in Hailey-Hailey disease and possible roles of SPCA1 isoforms in membrane trafficking.

ATP2C1 gene codes for the secretory pathway Ca2+/Mn2+-ATPase pump type 1 (SPCA1) localizing at the golgi apparatus. Mutations on the human ATP2C1 gene, 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 the ATP2C1 gene 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.

Hailey-Hailey disease: A fold (intertriginous) dermatosis

Hailey-Hailey disease, also called benign familial pemphigus, is a late-onset blistering disorder that affects the flexures. There are typically painful erosions and cracks in affected areas. Lesions generally begin between 20 and 40 years of age. In two third of all cases, positive family history is detected. In pathogenesis, there is a defect in keratinocyte adhesion due to ATP2 C1 gene mutation. The result of the desmosomal decomposition is acantholysis. Menstruation, pregnancy, skin infections, physical trauma, excessive sweating and exposure to ultraviolet radiation are important triggering factors. Histopathologic changes are suprabasal acantholysis and formation of intraepidermal bullae. In the epidermis, a partial acantholysis that looks like broken bricks is observed.

Mutation‐dependent effects on mRNA and protein expressions in cultured keratinocytes of Hailey–Hailey disease

Hailey-Hailey disease (HHD) is a dominantly inherited skin disease caused by mutations in ATP2C1 gene, which encodes secretory pathway Ca(2+) /Mn(2+) -ATPase protein 1. The precise mechanism remains unclear. In this study, to understand molecular basis of HHD, we examined expression of mRNA and protein in cultured keratinocytes derived from three HHD patients with different mutations. We showed that reduced expression of mRNA and protein in patient with p.Gln504X, but not in patients with p.Pro307His and c.1308+1G>A. RT-PCR analysis for patient with c.1308+1G>A revealed in-frame exon skipping. Reduction of mRNA and protein in p.Gln504X was considered to be caused by nonsense-mediated mRNA decay. p.Pro307His located adjacent to Ca(2+) -binding residue may induced conformational change, which leads to defective Ca(2+) transport. In-frame shorter transcript caused by c.1308+1G>A may have slightly reduced activity, which accounted for mild phenotype of the patient. These results clarified the pathogenic effects of different causative mutations in development of skin lesions.

Hailey-Hailey Disease Treated with Topical Tacalcitol

Dear Editor: Hailey-Hailey disease (HHD) is a hereditary blistering skin disease, transmitted in an autosomal dominant way with variable genetic penetrance1. It affects the intertriginous skin, and has a chronic, relapsing-remitting course. Although various medical treatments, including topical and systemic corticosteroids, antifungals, and antibiotics have been reported, there is no radically curative therapy for HHD. Recently, 1α,25-dihydroxyvitamin D3 have demonstrated considerable efficacy for treating HHD2. In addition, another vitamin D3 derivate, 1α,24-dihydroxyvitamin D3 (tacalcitol), was also topically effective on HHD lesions in vivo and in vitro3. We report an interesting case of HHD which was successfully treated with topical tacalcitol. A 54-year-old Korean man was presented with a 10-year history of recurrent skin lesions on both axillae. The patient had been previously diagnosed as having chronic eczema and treated with various types of treatment, such as topical and oral corticosteroids, topical and oral antibiotics, and oral antihistamines for several years in other clinics. However, his lesions were resistant to the treatments. His mother and brother also had similar skin lesions. The results of routine laboratory tests were essentially normal. On physical examination, large erythematous, superficial, crusted erosions were noted on both axillae (Fig. 1A). A histological examination revealed typical features of HHD, including intraepidermal clefts of various sizes in the epidermis, as well as characteristics of incomplete acantholysis in large parts of the epidermis, giving the appearance of a 'dilapidated brick wall' (Fig. 2). Clinicopathological findings established the diagnosis of HHD. For treatments, 0.002% tacalcitol ointment was topically applied to the lesions twice daily. After a month, the lesions treated with topical tacalcitol resolved, and only a few papules and erythema remained (Fig. 1B). Fig. 1 (A) Clinical photograph of the present case at first visit. (B) Clinical photograph of the present case at one month after topical tacalcitol treatment. Fig. 2 Histopathologic findings of the lesional skin showing intraepidermal clefts with irregular acantholysis giving a 'dilapidated brick wall appearance' (H&E, ×100). To date, there are very few recent reports on the use of topical vitamin D3 derivatives, such as topical tacalcitol or calcitriol in HHD2,3. The exact mechanism of action of topical vitamin D3 derivatives in HHD is not clear. It is hypothesized that the main reason for the pathologic changes of HHD is an altered protein composition of desmosomes leading to acantholysis which derives from ATP2C1 gene mutations localized on chromosome 3q21-q244,5. The ATP2C1 gene codes a Ca2+-pump that regulates the transportation of calcium from the cytosol into the Golgi apparatus4,5. This Ca2+-pump may play an important role in the intracellular Ca2+ signaling and homeostasis, and a malfunction of this pump may disturb cell-cell adhesion and the differentiation of the epidermal keratinocytes4,5. Our experience seems to indicate that tacalcitol, mostly affecting the calcium gradient in differentiating keratinocytes, could regulate and preserve the desmosome assembly and integrity in HHD. In conclusion, our case demonstrated that topical tacalcitol could be considered a therapeutic option for treating and maintaining the inherited disorder. But, the results on a single patient are often difficult to interpret. Therefore, further studies are needed to confirm the efficacy of topical vitamin D3 analogs for the treatment of HHD.

Detection and comparison of two types of ATP2C1 gene mutations in Chinese patients with Hailey–Hailey disease

The gene ATP2C1 is identified as the defective gene in Hailey-Hailey disease (HHD). The nonsense and missense are two common types of mutations and have, respectively, been detected in many HHD patients. The aims of our study were to identify the pathogenic ATP2C1 abnormality in Chinese HHD patients, and to compare nonsense and missense mutations in vivo to provide further understanding of the molecular and the physiological basis of HHD. The nucleotide sequencing of the ATP2C1 gene was performed in HHD patients, unaffected family members and 100 unrelated individuals. Meanwhile, we detected and analyzed the clinical manifestations, the expression of ATP2C1 mRNA and hSPCA1 protein in the two types of mutations. Three heterozygous mutations were identified, including a previously reported nonsense mutation (R799X), two novel missense mutations (D644G) and (R417K). The results of comparisons between two types of mutations showed that the common clinical features, the similarly low-level expressions of ATP2C1 mRNA and hSPCA1 protein, but the ATP2C1 mRNA expression of nonsense mutation was lower than missense mutation and even less than half the level of normal people. Our findings expand the known spectrum of ATP2C1 mutations in HHD. We supported the haploinsufficiency theory as prevalent mechanism in both types of mutations, and believed that the differences of ATP2C1 mRNA expressions in peripheral blood may relate with the type of mutation and reflect the state of illness of patients.

Analysis of ATP2C1 gene mutations in Chinese patients with Hailey-Hailey disease

Analysis of ATP2C1 gene mutations in Chinese patients with Hailey-Hailey disease

A Case of Hailey–Hailey Disease in an Infant with a New ATP2C1 Gene Mutation

Familial benign chronic pemphigus or Hailey-Hailey disease (OMIM 169600) is an autosomal-dominant blistering disease. Here we present a rare case of familial benign chronic pemphigus in a Chinese infant. The 5-month-old proband, who showed diffusely distributed skin lesions, is the youngest patient of Hailey-Hailey disease ever reported. The detection of an ATP2C1 gene mutation in this infant confirmed the diagnosis. His mother carried the same mutation, but with no history of skin lesions.

Heterogeneous mutations of the ATP2C1 gene causing Hailey–Hailey disease in Hong Kong Chinese

Hailey-Hailey disease (HHD) is a rare autosomal dominant dermatosis. It causes suprabasilar acantholysis leading to vesicular and crusted erosions affecting the flexures. Mutation of ATP2C1 gene encoding the human secretory pathway Ca(2+) /Mn(2+) -ATPase (hSPCA1) was identified to be the cause of this entity. The aim of this study was to study the mutational profile of the ATP2C1 gene in Hong Kong Chinese patients with HHD. Patients with the clinical diagnosis of HHD proven by skin biopsy were included in this study. Mutation analysis was performed in 17 Hong Kong Chinese patients with HHD. Ten mutations in the ATP2C1 gene were found. Six of these were novel mutations. The novel mutations included a donor splice site mutation (IVS22+1G>A); a missense mutation (c.1049A>T); two deletion mutations (c.185_188delAGTT and c.923_925delAAG); an acceptor splice site mutation (IVS21-1G>C) and an insertion mutation (c.2454dupT). The six novel mutations provide additions to the HHD mutation database. No hot-spot mutation was found and high allelic heterogeneity was demonstrated in the Hong Kong Chinese patients.

Mutation analysis of ATP2C1 gene in a Chinese family with Hailey-Hailey disease

To study a Chinese pedigree with Hailey-Hailey disease (HHD) and identify the ATP2C1 gene mutation in this family. All exons of the ATP2C1 gene were analyzed with polymerase chain reaction and DNA sequencing in all patients of this family and 80 unrelated population-matched controls. We identified a nonsense mutation 163C to T, resulting in a premature termination codon in ATP2C1 gene. The mutation was not found in normal individuals of the family and controls. The mutation can affect the result of transcription and translation of ATP2C1 gene, and it is firstly reported in the Chinese pedigree with HHD.

Mutation analysis of ATP2C1 gene in patients with Hailey-Hailey disease

Objective To detect the mutations in ATP2C1 gene of 5 sporadic patients with Hailey-Hailey disease (HHD).Methods Five sporadic patients with HHD collected from the outpatient clinic setting were recruited into this study with informed consent.Blood samples were taken from all patients and 100 unrelated human controls.and DNA was extracted from these samples.Mutation scanning was carried out for ATP2C1 gene by polymerase chain reaction (PCR) and direct sequencing.Results The diagnosis of all cases was confirmed by typical clinical manifestation,cutaneous pathology and immunofluorescence pathology.Five novel mutations.including a deletion mutation (2025delG),three missence mutations (L269R,C348R,A651D) and a non-sense mutation (Q259X) were identified in these cases.No mutations were detected in any of the 100 controls.Conclusion Five novel mutations in ATP2C1 gene have been identified for Hailey-Hailey disease. Key words: Pemphigus,benign familial; Genes,ATP2C1; Mutation

Mutation analysis of the ATP2C1 gene in Taiwanese patients with Hailey-Hailey disease

Hailey-Hailey disease (HHD) is an autosomal dominant disorder with recurrent pruritic vesicles and erosions, and scaly erythematous plaques, particularly involving intertriginous areas such as the neck, axillae, groins and perineum. Histopathology shows intraepidermal vesiculation with acantholysis in the suprabasal layer. It is caused by heterozygous mutations in the ATP2C1 gene, which encodes for the human secretory pathway Ca 2+ /Mn 2+ ATPase 1. In this study, we analyze the mutations of the ATP2C1 gene in 26 Taiwanese patients with HHD. In total, 21 familial cases from seven families and 5 sporadic cases (including 7 previously reported) were retrieved from the medical records. The diagnosis of HHD was made based on the characteristic clinical features and histopathological evidence. All 27 exons and flanking intron boundaries were amplified by polymerase chain reaction and the products were analyzed by direct sequencing. We identified three nonsense mutations (R39X, R468X, R783X), two splice-site mutations (483 + 2t→a, 832G→A), four deletion mutations (nt884-904del, 1459delCTCA, 1874delA, 1975delA) and one missense mutation (A730T). Two unrelated families with nonsense mutation R783X had the comorbidity of chronic schizophrenia since the third decade. We report two novel mutations (832G→A and 1874delA) of ATP2C1 involved in HHD. The nonsense mutation R783X might represent a mutational “hotspot” in the ATP2C1 gene. The present study demonstrates that a spectrum of ATP2C1 gene mutations is present in Taiwanese HHD patients.

A novel mutation of ATP2C1 gene in a Chinese pedigree with Hailey-Hailey disease.

Objective To detect the mutation of ATP2C1 gene in a Chinese pedigree with Hailey-Hailey disease (HHD). Methods A total of 9 family members from a Chinese three-generation pedigree were investigated. Characteristic manifestations of HHD were noted in 2 of the family members. Blood samples were collected from all family members of this pedigree and 100 unrelated healthy controls. Genomic DNA was extracted from peripheral blood cells and subjected to amplification of 27 exons of ATP2C1 gene fol-lowed by DNA sequencing. Results An unreported missence mutation (M661R) was identified in the 2 family members suffering from HHD, but not in the remaining family members or unrelated controls. Con-clusion A specific novel mutation( M661R) in ATP2C1 gene is identified in a Chinese pedigree with HHD. Key words: Pemphigns; benign familial; Mutation; ATP2C1 gene

Familial benign pemphigus

Familial benign pemphigus (HHD) is a rare autosomal dominant inherited disorder characterized by recurrent multiple vesicles and bullae predominantly localized in body folds. In 2000, it was confirmed that HHD is caused by a heterozygous mutation in the ATP2C1 gene, which encodes the human secretory pathway Ca2+/Mn2+-ATPase protein 1 (hspcA1). At present, more than 100 kinds of mutation points have been detected. This paper offers an update on the knowledge about the etiology, patbogenesis, clinical manifestations, histopathoiogy, treatment of HHD, so as to provide a theoretic basis for the research of HHD. Key words: Pemphigus, benign familial; Genes; Mutation

Genetic diagnosis in a Chinese Hailey–Hailey disease pedigree with novel ATP2C1 gene mutation

Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characterized by recurrent eruption of vesicles and bullae at the sites of friction and in the intertriginous areas. Mutations in the ATP2C1 gene encoding the human secretory pathway calcium ATPase 1 (hSPCA1) have been identified as the causative mutations in HHD. In this study, we used direct sequencing and restriction endonuclease digestion to analyze mutations of the ATP2C1 gene in a Chinese three-generation pedigree. A heterozygous T-to-C transition at nucleotide 1004 in exon 12 of ATP2C1 gene was detected. After summarizing the reported cases with ATP2C1 mutation, we concluded that the T1004C transition resulted in a novel missense mutation of leucine condon (CTG) to proline (CCG) at amino acid residue 335(L335P) in hSPCA1. Here, a genetic diagnosis was made for the proband's daughter before the clinical presentation. The study realized the molecular diagnosis in the HHD pedigree. Our findings should be useful for genetic counseling and prenatal diagnosis for the affected family and in demonstrating the critical role of the ATP2C1 gene in the pathogenesis of HHD further.