Darier disease: first molecular study of a Portuguese family
Background: Darier disease (DD) is a rare autosomal dominant condition characterized by skin lesions. Additionally, a wide range of neuropsychiatric symptoms is frequently reported in DD patients. This genodermatosis relies on mutations in the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transport...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-09-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844019361808 |
| _version_ | 1818279531571576832 |
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| author | Andreia Almeida Maria de Lurdes Lobo Cecília Moura Isabel Rivera |
| author_facet | Andreia Almeida Maria de Lurdes Lobo Cecília Moura Isabel Rivera |
| author_sort | Andreia Almeida |
| collection | DOAJ |
| description | Background: Darier disease (DD) is a rare autosomal dominant condition characterized by skin lesions. Additionally, a wide range of neuropsychiatric symptoms is frequently reported in DD patients. This genodermatosis relies on mutations in the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 (ATP2A2) gene, which encodes an ATPase responsible for pumping Ca2+ from the cytosol to the lumen of the ER. Objective: Herein we studied the molecular aspect of a two-generation Portuguese family with DD history with clinical variability. Methods: All exons and intron-exon borders of genomic ATP2A2, as well as coding ATP2A2, were sequenced. Relative levels of SERCA2 mRNA and protein were quantified by qPCR and western blotting, respectively. Results: The c.1287+1G > T variant was identified in all affected individuals, whereas the unaffected individual was shown to carry the wild-type ATP2A2 sequence in both alleles. This variant leads to the skipping of full exon 10, which consequently generates a frameshift originating a premature STOP codon in exon 11 (p.V395 = fs*19). Although the mutant mRNA seems to partially escape degradation, results suggest synthesis inhibition or immediate degradation of the mutant protein. Neuropsychiatric and other occurrences affecting certain patients are also reported. Conclusion: This is the first study of DD in Portugal, the variant identified, previously described in a single Japanese patient, may be considered a pathogenic mutation, and haploinsufficiency the mechanism underlying DD pathology in these patients. This study also highlights the co-occurrence of neuropsychiatric features in DD. |
| first_indexed | 2024-12-12T23:34:49Z |
| format | Article |
| id | doaj.art-f5f4364f146248fcb1109b8894e5403c |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-12-12T23:34:49Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-f5f4364f146248fcb1109b8894e5403c2022-12-22T00:07:34ZengElsevierHeliyon2405-84402019-09-0159e02520Darier disease: first molecular study of a Portuguese familyAndreia Almeida0Maria de Lurdes Lobo1Cecília Moura2Isabel Rivera3Metabolism & Genetics Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, PortugalCentro Hospitalar Universitário de Lisboa Central, PortugalDepartment of Dermatology, Instituto Português de Oncologia de Lisboa Francisco Gentil, PortugalMetabolism & Genetics Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Portugal; Departments of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Portugal; Corresponding author.Background: Darier disease (DD) is a rare autosomal dominant condition characterized by skin lesions. Additionally, a wide range of neuropsychiatric symptoms is frequently reported in DD patients. This genodermatosis relies on mutations in the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 (ATP2A2) gene, which encodes an ATPase responsible for pumping Ca2+ from the cytosol to the lumen of the ER. Objective: Herein we studied the molecular aspect of a two-generation Portuguese family with DD history with clinical variability. Methods: All exons and intron-exon borders of genomic ATP2A2, as well as coding ATP2A2, were sequenced. Relative levels of SERCA2 mRNA and protein were quantified by qPCR and western blotting, respectively. Results: The c.1287+1G > T variant was identified in all affected individuals, whereas the unaffected individual was shown to carry the wild-type ATP2A2 sequence in both alleles. This variant leads to the skipping of full exon 10, which consequently generates a frameshift originating a premature STOP codon in exon 11 (p.V395 = fs*19). Although the mutant mRNA seems to partially escape degradation, results suggest synthesis inhibition or immediate degradation of the mutant protein. Neuropsychiatric and other occurrences affecting certain patients are also reported. Conclusion: This is the first study of DD in Portugal, the variant identified, previously described in a single Japanese patient, may be considered a pathogenic mutation, and haploinsufficiency the mechanism underlying DD pathology in these patients. This study also highlights the co-occurrence of neuropsychiatric features in DD.http://www.sciencedirect.com/science/article/pii/S2405844019361808GeneticsDarier diseaseATP2A2SERCA2Mutational analysis |
| spellingShingle | Andreia Almeida Maria de Lurdes Lobo Cecília Moura Isabel Rivera Darier disease: first molecular study of a Portuguese family Heliyon Genetics Darier disease ATP2A2 SERCA2 Mutational analysis |
| title | Darier disease: first molecular study of a Portuguese family |
| title_full | Darier disease: first molecular study of a Portuguese family |
| title_fullStr | Darier disease: first molecular study of a Portuguese family |
| title_full_unstemmed | Darier disease: first molecular study of a Portuguese family |
| title_short | Darier disease: first molecular study of a Portuguese family |
| title_sort | darier disease first molecular study of a portuguese family |
| topic | Genetics Darier disease ATP2A2 SERCA2 Mutational analysis |
| url | http://www.sciencedirect.com/science/article/pii/S2405844019361808 |
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