OBJECTIVE: To explore the clinical phenotype and genetic characteristics of a Chinese Han pedigree with Darier's disease (DD). METHODS: A DD pedigree, who visited Tongji Hospital of Tongji University on October 22, 2023, was selected as the study subject. Clinical data of the pedigree were collected, and whole exome sequencing was performed on the proband. Suspected variant loci were screened, and Sanger sequencing was used to validate the variant in pedigree members. Bioinformatics analysis was performed on the variant loci. This study was approved by the Medical Ethics Committee of Tongji Hospital of Tongji University Ethics No.K-W-2024-004). RESULTS: The proband is a 67-year-old female with clinical features of DD, such as keratotic papules in sebaceous areas. whole exome sequencing revealed a missense variant, c.68G>A (p.Gly23Glu), in the exon 1 of ATP2A2 gene of the proband. Sanger sequencing showed that the proband's eldest daughter also carried this variant. This variant was not detected in other pedigree members, indicating a co-segregation of the variant with the disease phenotype in the pedigree. According to the interpretation principles of gene variants by the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic (PS1+PM1+PM2_Supporting+PP1+PP3+PP4). CONCLUSION The c.68G>A (p.Gly23Glu) variant in the ATP2A2 gene may be the genetic cause of the disease in this pedigree. This finding further enriches the genetic variant spectrum in DD patients and provides a basis for clinical diagnosis and genetic counseling for patients.
Aged ; Female ; Humans ; Male ; China ; Darier Disease/genetics* ; Exome Sequencing ; Mutation, Missense ; Pedigree ; Phenotype ; East Asian People ; Sarcoplasmic Reticulum Calcium-Transporting ATPases

OBJECTIVE: To explore the molecular basis for a pedigree affected with Darier-White disease. METHODS: Genomic DNA was isolated from 3 patients and 1 unaffected member from the pedigree, as well as 80 healthy controls. Targeted sequence capture and next-generation sequencing were used to screen mutations of skin disease-related genes. Candidate mutations were verified by Sanger sequencing, and co-segregation analysis was carried out to confirm the pathogenicity of mutation. Conservation analysis and protein structure and function were also predicted with Bioinformatic tools. RESULTS: A heterozygous mutation c.2246G>T (p.G749V) was identified in exon 15 of ATP2A2 gene in all 3 patients from the pedigree, but not in the unaffected member or 80 healthy controls. The corresponding amino acid was highly conserved, and mutation of which can lead to structural and functional changes of the protein. CONCLUSION The c.2246G>T missense mutation of the ATP2A2 gene probably underlies the Darier-White disease in this pedigree by causing damages to the structure and function of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2).
Darier Disease ; genetics ; Heterozygote ; Humans ; Mutation, Missense ; Pedigree ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; genetics

OBJECTIVETo detect mutations of ATP2A2 gene in a pedigree and a sporadic case with Darier disease (DD) and explore the underlying molecular mechanism.

METHODSClinical data of the pedigree and the sporadic case were collected. Genomic DNA was extracted from blood samples of four members from the pedigree (including three patients and one healthy member), the sporadic case and 100 healthy controls. PCR was performed to amplify all coding exons of the ATP2A2 gene. And the products were directly sequenced to detect mutations.

RESULTSA missense mutation c.1484C>T (p.S495L) in exon 12 was detected in all patients of the pedigree. For the sporadic case, a novel splicing mutation c.325-2A>G was detected at the junction between intron 4 and exon 5. The same mutations were not found in the 100 healthy controls.

CONCLUSIONMutations of the ATP2A2 gene may lead to the occurrence of DD in both familial and sporadic cases with DD.

Aged ; Alternative Splicing ; genetics ; Base Sequence ; Child ; DNA Mutational Analysis ; Darier Disease ; genetics ; Family Health ; Female ; Genetic Predisposition to Disease ; genetics ; Humans ; Male ; Mutation, Missense ; Pedigree ; Point Mutation ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; genetics