Darier Disease (DD) is a rare autosomal dominant genodermatosis (prevalence: 1/30.000-100.000) characterized by hyperkeratotic papules in seborrheic areas, palmoplantar pits, distinctive nail dystrophy and in some cases neurological symptoms. ATP2A2, encoding for the sarco/endoplasmic reticulum calcium transporting ATPase2 (SERCA2), is the causative gene of DD. It is characterized by high penetrance but variable expressivity and the onset is usually in childhood/puberty. A cohort of 50 suspected DD subjects have been analysed by the Medical Genetics Unit of 'Mauro Baschirotto' Institute for Rare Diseases. We found ATP2A2 genetic variations in 48% (n = 24/50) of the tested subjects carrying 22 heterozygous genetic variations: 41% missense variants (n = 9/22), 32% nonsense variants (n = 7/22), 9% in/del variants (n = 2/22), 9% intronic variants (n = 2/22), one deletion in an exon splicing site, and one variant at the 5 ' UTR. Of the 22 variants 13 were firstly discovered by this study. Among the 13 novel variants the 5 missense variants (p.Trp36Gly, p.Glu90Val, p.Ile315Phe, p.Gly354Arg and p. Val620Phe) were analyzed using nine computational tools (SIFT, Polyphen2, PROVEAN, FATHMM, PSEP, CADD, REVEL, AlphaMissense and DynaMut). The variants were reported as deleterious by all the computational tools suggesting an important impact of these variants on the structure/function of SERCA2. We obtained discordant results only for the p.Trp36Gly variant, but according to PSEP, this residue is the less conserved among the tested ones. We hypothesized that this could be the explanation for the contradictory in silico predictions. We identified 1 novel indel (p.Ala305Serfs*5) and 3 novel nonsense (p.Glu238*, p.Glu486*, p.Ser553*) genetic variations all leading to the formation of a premature stop codon. We found 1 novel variant in the 5 ' UTR (c.-161G >A), 2 novel intronic variants (c.545-3T>G; c.2318+2T>C) and 1 variant in an exon-intron boundary (c.2315_2318del) which probably affect splicing. Our results provide new insights to expand the spectrum of the ATP2A2 gene variations.
Expanding the spectrum of Darier Disease variants: 13 novel ATP2A2 genetic variations discovered in an Italian retrospective analysis / Stefani, C.; De Gemmis, P.; Cattelan, P.; Tibaudo, L.; Stagni, C.; De Sensi, E.; Ambrosini, E.; Percesepe, A.; Segat, D.; Lonigro, I.. - In: GENE. - ISSN 0378-1119. - 990:(2026). [10.1016/j.gene.2026.150071]
Expanding the spectrum of Darier Disease variants: 13 novel ATP2A2 genetic variations discovered in an Italian retrospective analysis
Stefani C.;De Sensi E.;Percesepe A.;Lonigro I.
2026-01-01
Abstract
Darier Disease (DD) is a rare autosomal dominant genodermatosis (prevalence: 1/30.000-100.000) characterized by hyperkeratotic papules in seborrheic areas, palmoplantar pits, distinctive nail dystrophy and in some cases neurological symptoms. ATP2A2, encoding for the sarco/endoplasmic reticulum calcium transporting ATPase2 (SERCA2), is the causative gene of DD. It is characterized by high penetrance but variable expressivity and the onset is usually in childhood/puberty. A cohort of 50 suspected DD subjects have been analysed by the Medical Genetics Unit of 'Mauro Baschirotto' Institute for Rare Diseases. We found ATP2A2 genetic variations in 48% (n = 24/50) of the tested subjects carrying 22 heterozygous genetic variations: 41% missense variants (n = 9/22), 32% nonsense variants (n = 7/22), 9% in/del variants (n = 2/22), 9% intronic variants (n = 2/22), one deletion in an exon splicing site, and one variant at the 5 ' UTR. Of the 22 variants 13 were firstly discovered by this study. Among the 13 novel variants the 5 missense variants (p.Trp36Gly, p.Glu90Val, p.Ile315Phe, p.Gly354Arg and p. Val620Phe) were analyzed using nine computational tools (SIFT, Polyphen2, PROVEAN, FATHMM, PSEP, CADD, REVEL, AlphaMissense and DynaMut). The variants were reported as deleterious by all the computational tools suggesting an important impact of these variants on the structure/function of SERCA2. We obtained discordant results only for the p.Trp36Gly variant, but according to PSEP, this residue is the less conserved among the tested ones. We hypothesized that this could be the explanation for the contradictory in silico predictions. We identified 1 novel indel (p.Ala305Serfs*5) and 3 novel nonsense (p.Glu238*, p.Glu486*, p.Ser553*) genetic variations all leading to the formation of a premature stop codon. We found 1 novel variant in the 5 ' UTR (c.-161G >A), 2 novel intronic variants (c.545-3T>G; c.2318+2T>C) and 1 variant in an exon-intron boundary (c.2315_2318del) which probably affect splicing. Our results provide new insights to expand the spectrum of the ATP2A2 gene variations.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
