ABSTRACT
Darier disease (DD) is a type of inherited keratinizing disorder that exhibits autosomal dominant inheritance. DD is caused by the mutations of ATP2A2, which encodes an endoplasmic reticulum calcium pump, sarco/endoplasmic reticulum ATPase type 2 (SERCA2). DD often develops in childhood, persists through adolescence, and causes small papules predominantly in seborrheic areas such as the face, chest and back. Further, scales and scabs may gradually develop. DD may be accompanied by non-dermal symptoms, including psychiatric symptoms. Histologically, DD is characterized by corps ronds and grains in addition to suprabasal cleavage. There are no currently validated curative treatments available for DD, with the majority of cases treated symptomatically. Despite demonstrating efficacy in the treatment of DD, the use of oral retinoids has been limited due to the association with various adverse effects.
Subject(s)
Darier Disease , Darier Disease/diagnosis , Darier Disease/genetics , Darier Disease/therapy , Diagnosis, Differential , Humans , Mutation , Sarcoplasmic Reticulum Calcium-Transporting ATPases/geneticsSubject(s)
Keratinocytes/metabolism , Keratinocytes/radiation effects , Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Darier Disease/genetics , Darier Disease/metabolism , Darier Disease/therapy , Down-Regulation/drug effects , Down-Regulation/radiation effects , Humans , Keratinocytes/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , Receptors, Prostaglandin E, EP4 Subtype/genetics , Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics , Ultraviolet Rays , Ultraviolet TherapyABSTRACT
The high affinity immunoglobulin E (IgE) receptor (FcεRI) plays a key role in the pathogenesis of atopy and allergic disorders. Several polymorphisms located in 5'-flanking region and 5'-untranslated region (5'-UTR) of human FCER1A, the gene encoding FcεRI α-subunit, have been shown to functionally affect its transcriptional activity. All those genetic variants have been also associated with allergic diseases and/or serum IgE levels. In the present study, we sought to identify functional polymorphisms in human FCER1A 3'-untranslated region (3'-UTR), the potential candidates for future genetic association studies. Search for polymorphisms within human FCER1A 3'-UTR region, conducted in Japanese and Poles, revealed the presence of +5650A>G and +5714G>A variants. Subsequently, structure/distribution of haplotypes and LD measures were analyzed in Japanese and Poles for both 3'-UTR variants and the functional polymorphisms located in 5'-flanking region and 5'-UTR of human FCER1A. Additionally, reporter plasmids containing human FCER1A main promoter and 3'-UTR with all four possible combinations of +5650A>G and +5714G>A polymorphisms were constructed to evaluate functional potential of both 3'-UTR variants. However, no genotype-related differences in the gene expression were observed, as measured by reporter activity in cultured human basophil/mast cell-like KU812 cells, suggesting that both +5650A>G and +5714G>A have no genotype-related functional effect. In summary, we described linkage disequilibrium and the distribution of haplotypes for two identified human FCER1A 3'-UTR polymorphisms and several previously reported 5'-flanking region and 5'-UTR variants in Japanese and Poles, representative for East Asians and Caucasians, the two ethnic groups in which genetic associations between FCER1A and allergic diseases and/or serum IgE levels have been previously reported.