What is the pathophysiology of keratosis follicularis (Darier disease)?

Updated: Jul 31, 2018
  • Author: Pui-Yan Kwok, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Answer

Mutations in the gene ATP2A2 cause keratosis follicularis (Darier disease). ATP2A2, located on 12q23-24.1, encodes the sarcoplasmic/endoplasmic reticulum Ca2+ -ATP isoform 2 protein (SERCA2), which is a calcium pump. [1] This pump maintains a low cytoplasmic Ca2+ level by actively transporting calcium ions from the cytosol into the lumen of the endoplasmic reticulum. Although more than 120 familial and sporadic mutations in ATP2A2 have been identified in keratosis follicularis (Darier disease) patients, attempts at genotype-phenotype correlation have not been successful. Some authors have suggested that recurrent ATP2A2 p.(Pro602Leu) mutation differentiates acrokeratosis verruciformis of Hopf from the allelic condition Darier disease. [2]

Family members with confirmed identical ATP2A2 mutations can exhibit differences in the clinical severity of disease, suggesting that other genes or environmental factors affect the expression of keratosis follicularis (Darier disease). [3, 4] A wide variety of ATP2A2 mutations in Darier disease have been identified. [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]

The mechanisms by which specific ATP2A2 mutations impact the function of the ATP2A2 protein have been investigated using an in vitro model. [22] Investigators transfected a fibroblast cell line with 51 different mutations seen in keratosis follicularis (Darier disease) pedigrees. The investigators found that the resultant transfected cells showed defects in ATP2A2 protein expression (15 mutants), ATP hydrolysis (29 mutants), calcium transport (4 mutants), and calcium binding and kinetics (3 mutants). In a different study, in which researchers systematically analyzed mutations identical to those found in patients with Darier disease, mutant SERCA2 protein aggregates were found to cause stress to the endoplasmic reticulum, subsequently inducing cell apoptosis. [7] Thus, diverse biochemical mechanisms are responsible for altered protein function.

Although expressivity is variable, penetrance of keratosis follicularis (Darier disease) is high, estimated at 95%. Because the disease-causing mutations in ATP2A2 affect functional domains of the gene, the mechanism of autosomal dominant transmission is believed to be haploinsufficiency, in which a single wild-type functioning ATP2A2 is insufficient to prevent disease. No unique phenotype for genetic homozygotes has been reported.

Abnormal keratinocyte-keratinocyte adhesion and aberrant epidermal keratinization are the primary histologic features of keratosis follicularis (Darier disease). Electron microscopy reveals loss of desmosomes (epithelial intercellular junctions formed by membrane and submembrane protein complexes), breakdown of desmosome-keratin intermediate filament attachment, and perinuclear aggregates of keratin intermediate filaments. The mechanism by which decreased activity of the SERCA2 calcium pump leads to these changes is still under investigation. [23] However, a significant correlation exists between the clinical presentation of keratosis follicularis (Darier disease) and the intensity of histologic features. [24]


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