Novel ATP2A2 mutations in a large sample of individuals with Darier disease

Abstract

Darier disease (DD) is a rare autosomal dominantly inherited skin disorder caused by mutations in ATP2A2, which is expressed in both the skin and the brain and encodes for SERCA2. We have screened the coding regions of ATP2A2 in a total of 95 unrelated individuals with DD to identify the pathogenic mutations. We identified 66 potentially pathogenic mutations in ATP2A2 for 74 of the 95 individuals with DD of which 45 (68%) are thought to be novel. Forty-nine (74%) are unique to an individual and 17 (26%) were found in more than one individual or overlap with previously identified variants. The results suggest that mutations in ATP2A2 may not be as family-specific as first thought. The spectrum of mutations identified will inform understanding of the pathogenesis of DD.

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

“…All mutations found are scattered throughout the sequence of ATP2A2 , in accordance with other studies. For three novel mutations (c.1A>T, c.1761+2T>G, c.2699T>C (p.(Leu900Pro))), different variants at the same position were described previously (c.1A>G, c.1761+2T>C, c.2699T>G (p.(Leu900Arg)), respectively) [Ruiz‐Perez et al., ; Ikeda et al., ; Onozuka et al., ; Bchetnia et al., ; Shi et al., ; Green et al., ; ]. We found c.1A>G in two of our patients as well, so that mutations at position 1 have been described on six instances up to date [Ruiz‐Perez et al., ; Ikeda et al., ; Onozuka et al., ; Green et al., ].…”

Darier disease

“…In a recent report, 66 mutations in ATP2A2 were identified in 74 out of 95 DD patients, of which 68% were de novo mutations. 9 There are three paralogs of SERCA, SERCA1-3, encoded by ATP2A1-3, respectively. Mutations of SERCA1 cause Brody myopathy, a disorder of skeletal muscle contractions, 10 13,14 Haploinsufficiency is thought to underlie the autosomal dominant inheritance of DD.…”

Genes and Schizophrenia: From a Festschrift Seminar Honoring William T. Carpenter Jr, MD

“…Most notably, however, these alleles also explained significant, albeit modest, amounts of the variance in risk for bipolar disorder in 2 independent data sets, with no significant evidence observed for overlap with multiple nonpsychiatric disorders including diabetes and rheumatoid arthritis. These data suggesting polygenic overlap are supported by candidate gene studies implicating a bipolar disorder risk gene, CACNA1C, in risk for schizophrenia, 5 as well as a recent study from the Psychiatric Genomics Consortium (PGC) of over 60 000 subjects identifying shared loci across 5 disorders (autism spectrum disorders, attention deficit hyperactivity disorder, major depressive disorder, bipolar disorder, and schizophrenia), including CACNA1C. 6 Taken together, these recent studies provide considerable evidence that a proportion of alleles that increase risk for schizophrenia are not specific to schizophrenia but also impart risk for other psychiatric disorders, including bipolar disorder.…”