Article

Autosomal-Dominant Calcium ATPase Disorders

1Department of Dermatology, University of Pécs, Pécs, Hungary.
Journal of Investigative Dermatology (Impact Factor: 7.22). 12/2006; 126(11):2370-6. DOI: 10.1038/sj.jid.5700447
Source: PubMed

ABSTRACT

Darier disease (DD) and Hailey-Hailey disease (HHD) are the only known autosomal-dominant Ca2+ ATPase disorders. Epidermal symptoms selectively occur in the affected individuals, the precise reason for which is still not fully understood. Here, we review the clinical, epidermal, and molecular features of the two genodermatoses. It is concluded that epidermal Ca2+ regulation disturbances and epigenetic factors may play an even more prominent role in the pathogenesis of DD and HHD than earlier appreciated.

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Available from: Richard Kellermayer, May 29, 2014
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    • "In previous researches, a spectrum of missense, frameshift , splice-site, and nonsense mutations have since been reported in ATP2C1. Among them, 20% are nonsense mutations, 30% are frame shift mutations leading to premature termination codons (PTCs), 28% are missense mutations [14]. 50% of mutations leading to PTCs points to haploinsufficiency as the predominant mechanism for HHD, but other researchers believe that missense mutations may cause HHD through the dominant negative mechanism [3]. "
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    ABSTRACT: 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.
    Full-text · Article · Nov 2011 · Archives for Dermatological Research
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    • "The most prominent characteristic of both HHD and DD, as discussed in numerous reviews [14] [65] [66] [67] [68], is the disruption of cell-cell contacts (acantholysis) in the suprabasal layer of the skin, which results from loss of desmosomal connections between cells. Ultrastructural studies of HHD [69] indicated that desmosomes and their connections with tonofilaments (keratin intermediate filaments) formed normally in non-lesional skin; however, in affected cells, tonofilaments separated from the desmosomes, followed by clumping of tonofilaments, loss of desmosomes, and acantholysis [69]. "
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    ABSTRACT: In mammalian tissues, uptake of Ca(2+) and Mn(2+) by Golgi membranes is mediated by the secretory pathway Ca(2+) -ATPases, SPCA1 and SPCA2, encoded by the ATP2C1 and ATP2C2 genes. Loss of one copy of the ATP2C1 gene, which causes SPCA1 haploinsufficiency, leads to squamous cell tumors of keratinized epithelia in mice and to Hailey-Hailey disease, an acantholytic skin disease, in humans. Although the disease phenotypes resulting from SPCA1 haploinsufficiency in mice and humans are quite different, each species-specific phenotype is remarkably similar to those arising as a result of null mutations in one copy of the ATP2A2 gene, encoding SERCA2, the endoplasmic reticulum (ER) Ca(2+) pump. SERCA2 haploinsufficiency, like SPCA1 haploinsufficiency, causes squamous cell tumors in mice and Darier's disease, also an acantholytic skin disease, in humans. The phenotypic similarities between SPCA1 and SERCA2 haploinsufficiency in the two species, and the general functions of the two pumps in consecutive compartments of the secretory pathway, suggest that the underlying disease mechanisms are similar. In this review, we discuss evidence supporting the view that chronic Golgi stress and/or ER stress resulting from Ca(2+) pump haploinsufficiencies leads to activation of cellular stress responses in keratinocytes, with the predominance of proapoptotic pathways (although not necessarily apoptosis itself) leading to acantholytic skin disease in humans and the predominance of prosurvival pathways leading to tumors in mice.
    Full-text · Article · May 2011 · BioFactors
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    • "Whether the pathological phenotype of the patients depends solely on the trans-Golgi Ca 2+ reduction, on the inefficiency of Mn 2+ homeostasis and/or on the alterations of Ca 2+ /Mn 2+ handling in the secretory granules is still debated. Indirect evidence , however, suggests that modifications of Mn 2+ uptake and secretory vescicle Ca 2+ handling is not primarily involved in the disease pathogenesis, as patients affected by the Darier's disease (due to mutated SERCA2 [64], a Ca 2+ pump that does not transport Mn 2+ and is excluded from the secretory vesicles) have skin symptoms that are very similar to those of the Hailey–Hailey patients [65]. We also found that a reduction in the SPCA1 level resulted in a drastic re-organization of the overall GA morphology and a delayed traffic of proteins from the ER into the GA and eventually to the plasma membrane [29]. "
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    ABSTRACT: The Golgi apparatus plays a central role in lipid and protein post-translational modification and sorting. Morphologically the organelle is heterogeneous and it is possible to distinguish stacks of flat cysternae (cis- and medial Golgi), tubular-reticular networks and vesicles (trans-Golgi). These morphological differences parallel a distinct functionality with a selective distribution and complementary roles of the enzymes found in the different compartments. The Golgi apparatus has been also shown to be involved in Ca(2+) signalling: it is indeed endowed with Ca(2+) pumps, Ca(2+) release channels and Ca(2+) binding proteins and is thought to participate in determining the spatio-temporal complexity of the Ca(2+) signal within the cell, though this role is still poorly understood. Recently, it has been demonstrated that the organelle is heterogeneous in terms of Ca(2+) handling and selective reduction of Ca(2+) concentration, both in vitro and in a genetic human disease, within one of its sub-compartment results in alterations of protein trafficking within the secretory pathway and of the entire Golgi morphology. In this paper we review the available information on the Ca(2+) toolkit within the Golgi, its heterogeneous distribution in the organelle sub-compartments and discuss the implications of these characteristics for the physiopathology of the Golgi apparatus.
    Full-text · Article · Feb 2011 · Cell calcium
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