Mutations in a single gene, ATP2A2, are responsible for the development of<unk> . ATP2A2 encodes the SERCA2 protein, which is a calcium pump localized to the membranes of the endoplasmic reticulum (ER) in nearly all cells and the sarcoplasmic reticulum (SR) in muscle cells. The ER is where protein processing and transport begins for proteins targeted for secretion. The SR is a specialized form of ER found in muscle cells that sequesters calcium, the regulated efflux of which into the cytosol stimulates muscle fiber contraction. Calcium acts as a second messenger in many cellular signal transduction pathways. SERCA2 is required for Ca2+ signaling in cells by removing nearly all Ca2+ ions from the cytoplasm and storing them in the ER/SR compartments. inheritance. A large number of mutant alleles of ATP2A2 have been identified in association with<unk> . One study of 19 families and 6 sporadic cases found 24 specific, novel mutations associated with DAR symptoms. This study reported a loose, imperfect correlation between the severity of ATP2A2 mutations with the severity of the condition. Significant variability in<unk>  severity between members of the same family carrying the same mutation was also reported by this study, suggesting that genetic modifiers contribute to the phenotypic penetrance of certain mutations. The mutation is inherited in an autosomal dominant pattern. This means that only one allele needs to be mutated in order to express the trait. This also means that someone who is born to one parent with DAR has a 50% chance of inheriting the mutant allele and having the<unk> . Loss-of-function mutations typically display recessive inheritance while the gain-of-function or hyperactive function of proteins is characteristic of dominant mutations. The observation that only one mutated allele of the SERCA2 is sufficient to produce clinical symptoms suggests that proper “gene dosage” is necessary for maintaining Ca2+ homeostasis in cells. This means that two wild type copies of ATP2A2 are needed for proper cell function, which provides a logical basis for dominant phenotypes arising from loss-of-function alleles. Most ATP2A2 mutations are haploinsufficiency mutations, which means that only having only one functional copy of the functional gene results in a reduced level of protein expression that is not sufficient for wild type function for making enough of the coded protein for the cell to function properly. However, there is significant variability in<unk>  severity in how the mutations are expressed even within families that have the same mutation. It is currently unclear in the current research why a reduction in SERCA2 expression/activity causes clinical symptoms restricted to the epidermis. One hypothesis that some researchers have given is that other cell types express additional “back-up” Ca2+ pumps that can compensate for the reduced function or expression of the SERCA2 protein, while skin cells rely exclusively on the SERCA2 gene for calcium sequestration, meaning only they are affected by its reduction in expression. As mentioned above, some cases of DAR result from somatic mutations to ATP2A2 in epidermal stem cells. These cases are referred to as instances of “linear”<unk> . Such individuals display phenotypic mosaicism, where the<unk> ’s phenotype only affects the subset of epidermal tissue arising from the mutated progenitor cell. Somatic mutations are not inherited by the offspring of such individuals.
Darier's disease
Bright's disease
Dent's disease
Minor's disease
Texier's disease
Chandler's disease
Tornwaldt's disease
Gorham's disease