ATP2C1

BET bromodomain inhibitors hold promise as therapeutic agents in diverse indications, but their clinical progression has been challenging and none have received regulatory approval. Early clinical trials in cancer have shown heterogeneous clinical responses, development of resistance, and adverse events. Increased understanding of their mechanism(s) of action and identification of biomarkers are needed to identify appropriate indication(s) and achieve efficacious dosing. Using genome-wide CRISPR-Cas9 screens at different concentrations, we report molecular mechanisms defining cellular responses to BET inhibitors, some of which appear specific to a single compound concentration...

Hailey-Hailey disease (HHD) is an autosomal dominant genetic disease caused by a mutation of the ATP2C1 gene. Corticosteroids, antibiotics or cyclosporine have been administered to reduce inflammation and prevent flare-ups, but the efficacy is not always sufficient. We herein report two cases of HHD effectively treated with apremilast and review the previous literature. Patient 1 was a 28-year-old male and patient 2 was a 35-year-old female. Both patients were diagnosed with HHD based on histological and genetic analyses...

Darier's disease (DD) and Hailey-Hailey disease (HHD), belonging to a hereditary acantholytic dermatosis caused by mutations in ATP2A2 and ATP2C1, respectively, are easily affected by eczema herpeticum (EH) induced by mostly herpes simplex virus (HSV) superinfection. However, the mechanisms by which those patients with DD or HHD are susceptible to HSV are not well elucidated. Here, we experienced two cases with DD, including three episodes of the exacerbation of DD after the development of severe EH. We serially measured serum cytokines before and after the development of EH and DD in these patients...

BACKGROUND: Hailey-Hailey disease (HHD) is an uncommon hereditary and benign skin condition characterized by blisters and erosions on intertriginous areas. It is related to a mutation of the ATP2C1 gene, which encodes a Ca2+ pump. It is characterized by multiple foci of skin acantholysis in the epidermis, with dyskeratosis and suprabasilar clefting. Galectin-3 is a beta galactoside binding protein that has an essential role in cell to cell and cell to matrix adhesion. We assessed galectin-3 immunohistochemical expression in HHD to explore its impact on the pathogenesis of this hereditary blistering disorder...

Nucleotide sugar transporters (NSTs) are ER and Golgi-resident members of the solute carrier 35 (SLC35) family which supply substrates for glycosylation by exchanging lumenal nucleotide monophosphates for cytosolic nucleotide sugars. Defective NSTs have been associated with congenital disorders of glycosylation (CDG), however, molecular basis of many types of CDG remains poorly characterized. To better understand the biology of NSTs, we identified potential interaction partners of UDP-galactose transporter (SLC35A2), UDP-N-acetylglucosamine transporter (SLC35A3) and an orphan nucleotide sugar transporter SLC35A4 of to date unassigned specificity...

Hailey-Hailey disease (HHD) is a rare autosomal dominant genodermatosis. It is characterized clinically by recurrent erosions, blisters and erythematous plaques at the sites of friction and intertriginous areas. The pathogenic gene of HHD was reported to be the ATPase calcium-transporting type 2C member 1 gene ( ATP2C1 ). In this study, genomic DNA polymerase chain reaction (PCR) and direct sequencing of ATP2C1 were performed from 3 Chinese pedigrees and 4 sporadic cases of HHD. We detected 3 heterozygous mutations, including 2 novel mutations (c...

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BACKGROUND AND OBJECTIVES: Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP. METHODS: Northern Europeans from UK Biobank comprising 6914 cases reporting pain all over the body lasting >3 months and 242 929 controls were studied...

Hailey-Hailey disease (HHD) is an autosomal dominant monogenic disease that is defective in the ATP2C1 gene. In previous studies, Sanger sequencing was the main method applied to detect mutations in HHD patients, and no mutations in the ATP2C1 gene were found in 12-55% of those reported. The aim of our study was to carry out whole exome sequencing (WES) for the HHD patients in whom efforts to identify mutations by Sanger sequencing had failed, and to find a new pathogenic gene. WES was performed using genomic DNA from 13 HHD patients and 364 in-house healthy controls...

BACKGROUND: Hailey-Hailey disease (HHD; OMIM: 169600) is an autosomal dominate genodermatosis, characterized by recurrent blisters and erosions clinically and remarkable acantholysis pathologically. The underlying pathogenic factor is the mutation of ATP2C1 gene (OMIM: 604384), which encodes secretory pathway Ca2+ /Mn2+ -ATPase (SPCA1). Skin folds are the predilection site of HHD. Atypical cases with a generalized pattern have rarely been reported, making it prone to misdiagnosis. METHODS: In this study, we presented three Chinese pedigrees of Hailey-Hailey disease with generalized skin lesions...

Hailey-Hailey disease (HHD) is genetic skin disorder characterized by repeated and exacerbated skin lesions in friction regions. ATP2C1 , encoding SPCA1, was demonstrated to be the responsible gene for HHD pathogenesis. However, for some cases, no ATP2C1 mutation could be determined by standard Sanger sequencing, thereby obscuring the cause and diagnosis of HHD. In this study, we investigated the possibility that HHD is caused by complex ATP2C1 defects using multiplex ligation-dependent probe amplification (MLPA) analysis for 10 of 50 cases in our institute without ATP2C1 mutations...

Adeno-associated viruses (AAVs) are dependoparvoviruses that have proven useful for therapeutic gene transfer; however, our understanding of host factors that influence AAV trafficking and transduction is still evolving. Here, we investigate the role of cellular calcium in the AAV infectious pathway. First, we demonstrate a critical role for the host Golgi-resident ATP-powered calcium pump (secretory pathway calcium ATPase 1; SPCA1) encoded by the ATP2C1 gene in AAV infection. CRISPR-based knockout (KO) of ATP2C1 decreases transduction by different AAV serotypes...

BACKGROUND: Familial benign chronic pemphigus, also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. The study aim to detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the possible mechnism of HHD pathogenesis by examining the expression profile of hSPCA1, miR-203, p63, Notch1 and HKII proteins in the skin lesions of HHD patients. METHODS: Genomic DNA was extracted from peripheral blood of HHD patients...

A 4-month-old female Irish Terrier presented with a well demarcated ulcerative and crusting lesion in the right ear canal. Histological analysis revealed epidermal hyperplasia with severe acantholysis affecting all suprabasal layers of the epidermis, which prompted a presumptive diagnosis of canine Darier disease. The lesion was successfully treated by repeated laser ablation of the affected epidermis. Over the course of three years, the dog additionally developed three dermal nodules of up to 4 cm in diameter that were excised and healed without complications...

TMEM165 is a Golgi protein whose deficiency causes a Congenital Disorder of Glycosylation (CDG). We have demonstrated that Mn2+ supplementation could suppress the glycosylation defects observed in TMEM165-deficient cells and that TMEM165 was a Mn2+ -sensitive protein. In the Golgi, the other transmembrane protein capable to regulate Mn2+ /Ca2+ homeostasis is SPCA1, encoded by the ATP2C1 gene. A loss of one copy of the ATP2C1 gene leads to Hailey-Hailey Disease (HHD), an acantholytic skin disorder in Humans...

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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...

AIMS: The physiological and pathological importance of hydrogen sulfide (H2S) as a novel gasotransmitter has been widely recognized. Cystathionine gamma-lyase (CSE) is one of major H2S-producing enzymes and regulates diverse functions in connection with intracellular calcium (Ca2+). The aim of the present study is to examine the role of H2S in Golgi stress-related cell injury and skeletal muscle disorders. RESULTS: Golgi stressors (brefeldin A and monensin) decreased the expressions of GM130 and ATP2C1 (two markers of Golgi stress response), induced Golgi apparatus fragmentation, and caused higher level of oxidative stress and cell apoptosis in mouse myoblast cells...

Hailey-Hailey disease (HHD) is a rare, chronic and recurrent blistering disorder, characterized by erosions occurring primarily in intertriginous regions and histologically by suprabasal acantholysis. Mutation of the Golgi Ca2+ -ATPase ATP2C1 has been identified as having a causative role in Hailey-Hailey disease. HHD-derived keratinocytes have increased oxidative-stress that is associated with impaired proliferation and differentiation. Additionally, HHD is characterized by skin lesions that do not heal and by recurrent skin infections, indicating that HHD keratinocytes might not respond well to challenges such as wounding or infection...

OBJECTIVE: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. METHODS: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions...