Darier's Disease: Mutation Analysis

Darier's disease (DD) is a rare dominantly inherited skin disorder characterized by warty papules and plaques in seborrheic areas (central trunk ,flexures, scalp and forehead) palmo-plantar pits and distinctive nail abnormalities.The prevalence of the disease has been estimated as 1/55,000 to 1/100,000. Although penetrance is high in adults, the expression of the disease is extremely variable. Involvement may be severe, with widespread itchy malodorous crustedplaques, painful erosions, blistering and mucosal lesions. Secondary infection is common. Sun, heat and sweating exacerbate the disease. DD never remits, but oral retinoids may reduce hyperkeratosis. DD has been reported to be associated with neuropsychiatric abnormalities including mild mental retardation and epilepsy in a few families .The typical histological features include focal areas of separation between suprabasal epidermal cells and abnormal keratinization. Immunohistopathology and electron microscopy reveal loss of desmosomal attachments and perinuclear aggregations of keratin filaments. These observations suggested that defects in a molecule involved in desmosome formation and/or stability could be implicated in the pathophysiology of the disease. Now, it has been demonstrated that ATP2A2,which encodes the sarco/endoplasmic reticulum Ca2+ ATPase isoform2 (SERCA2) belonging to the large family of P-type cation pumps that couple ATP hydrolysis with cation transport across membranes is the defective gene in DD. Although so far approximately 140 different ATP2A2 mutations, including missense, nonsense, frameshift, deletion/insertion and splice-site mutations have been reported in different forms of DD, no apparent relation between genotype/phenotype has emerged.In this study, we reported a three-generation family with DD, and examined ATP2A2 gene mutations in this family by direct sequencing. A novel missense mutation A-G was identified in exon 12, nucleotide 1704, which predicts to lead to the substitution of lysine by arginine at codon 514 (K514R). This study will contribute to expand database on ATP2A2 in DD, and further illustrate the extensive diversity of mutational events that led to the different phenotypes of DD.