Дариер ауруы: генетикалық себептері мен көріністері

Darier's disease (DAR) is a rare, inherited skin disorder that presents with multiple greasy, crusting, thick brown bumps that merge into patches. It is an autosomal dominant disorder discovered by French dermatologist Ferdinand Jean Darier. Mild forms of the disease are the most common, consisting solely of skin rashes that flare up under certain conditions such as high humidity, high stress, or tight fitting clothes. Short stature, when combined with poorly formed fingernails that contain vertical striations, is diagnostic even for mild forms of DAR. Symptoms will usually appear in late childhood or early adulthood between the ages of 15 and 30 years and will vary over the lifespan. More severe cases are characterized by dark crusty patches on the skin that are mildly greasy and that emit a strong odor. These patches, also known as keratotic papules, keratosis follicularis, or dyskeratosis follicularis, most often appear on the scalp, forehead, upper arms, chest, back, knees, elbows, and behind the ear.

Mutations in a single gene, ATP2A2, are responsible for the development of Darier's disease. 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. A large number of mutant alleles of ATP2A2 have been identified in association with Darier's Disease. 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 disease 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 disease. 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.

Diagnosis of Darier disease is often made by the appearance of the skin, family history, or genetic testing for the mutation in the ATP2A2 gene. However, many individuals are never diagnosed because of the mildness of their symptoms. Mild cases present clinically as minor rashes (without odor) that can become exacerbated by heat, humidity, stress, and sunlight. The symptoms of the disease are thought to be caused by an abnormality in the desmosome keratin filament complex leading to a breakdown in cell adhesion. [[File:Darier disease rash. jpg|thumb| Several case studies have suggested affected populations display elevated frequencies of learning disorders, but this has yet to be confirmed.

Worldwide prevalence is estimated as between 1:30,000 and 1:100,000. Case studies have shown estimated prevalence by country to be 3.8:100,000 in Slovenia, 1:36,000 in north east England, 1:30,000 in Scotland, and 1:100,000 in Denmark.

Darier's disease was first described by the dermatologist Ferdinand Jean Darier in the French dermatological journal Annales de dermatologie et de syphilographie. Darier was a well regarded dermatologist of the time who was the head of the medical department at the Hôpital Saint Louis. Darier was an early proponent of histopathology, or the examination of samples of diseased flesh under a microscope to determine the cause of illnesses. Using this technique, he was able to uncover the origins of Darier's disease and a host of others that also bear his name. James Clarke White, a dermatologist at Harvard Medical School, independently characterized and published his observations on this dermatological disorder in the same year as Darier (1889), which is why the condition is also referred to as Darier White disease.

In Singapore, there was a case of a man who escaped the death penalty for murder as a result of Darier's disease. 27 year old Ong Teng Siew, a Malaysian and chicken slaughterer, was charged with murdering a 82 year old opium addict Ng Gee Seh (alias Ng Ee Seng) in December 1995. Ong was sentenced to death in August 1996 after the trial court found him guilty of murder, and while he was in midst of appealing against his conviction and sentence, Ong was hospitalized in September 1996 for an outbreak of Darier's disease, which previously went undiagnosed before and during the trial, and after his lawyer Wong Siew Hong discovered that the disease had a causal link to various psychiatric disorders, the new evidence enabled Ong to successfully apply for a re trial for Ng's murder. After the trial court heard the new evidence, it accepted that at the time of the killing, Ong was suffering from diminished responsibility as a result of Darier's disease, and therefore, Ong was found guilty of a lesser offence of manslaughter and he was re sentenced to life imprisonment in April 1998.