Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey–Hailey Disease. Issue 4 (15th February 2017)

• Record Type: Journal Article
• Authors: Nellen, Ruud G.L.; Steijlen, Peter M.; van Steensel, Maurice A.M.; Vreeburg, Maaike; Frank, Jorge; van Geel, Michel
• Is Part Of: Human mutation. Volume 38:Issue 4(2017)
• Page Start: 343
• Page End: 356
• Publication Date: 2017-02-15
• Subjects: Darier disease -- Hailey–Hailey disease -- acrokeratosis verruciformis of Hopf -- ATP2A2 -- ATP2C1 -- SERCA2 -- SPCA1 -- locus‐specific database -- genotype–phenotype correlation; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23164
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : Defects in the enzyme argininosuccinate synthetase (ASS, also known as citrullinemia type 1) can lead to different phenotypes, ranging from life‐threatening neonatal hyperammonemia to a later onset with mild or no symptoms. We collected clinical data of >360 patients and reported 137 mutations (64 of which are novel): 89 missense mutations, 19 nonsense mutations, 17 mutations that affect splicing and 12 deletions. We reviewed as well ASS regulation, animal models, diagnostic strategies, newborn screening and treatment options. ABSTRACT: The two disorders of cornification associated with mutations in genes coding for intracellular calcium pumps are Darier disease (DD) and Hailey–Hailey disease (HHD). DD is caused by mutations in the ATP2A2 gene, whereas the ATP2C1 gene is associated with HHD. Both are inherited as autosomal‐dominant traits. DD is mainly defined by warty papules in seborrheic and flexural areas, whereas the major symptoms of HHD are vesicles and erosions in flexural skin. Both phenotypes are highly variable. In 12%–40% of DD patients and 12%–55% of HHD patients, no mutations in ATP2A2 or ATP2C1 are found. We provide a comprehensive review of clinical variability in DD and HHD and a review of all reported mutations in ATP2A2 and ATP2C1 . Having the entire spectrum of ATP2A2 and ATP2C1 variants allows us to address the question of a genotype–phenotype correlation, which has not been settled unequivocally in DD and HHD. We created a database for all mutations in ATP2A2 and ATP2C1 using the Leiden Open Variation Database (LOVD v3.0), for variants reported in the literature and future inclusions. This data may be of use as a reference tool in further research on treatment of DD and HHD.