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Pathogenic de novo variant in WRN induces exon skipping and underlies Werner Syndrome

ABSTRACT: Werner Syndrome, an autosomal recessive disorder associated with premature aging, results from mutations in the WRN gene. Patients exhibit susceptibility to tumors and pathological changes, including eye alterations, skin lesions, and hair thinning, along with complications such as diabetes, osteoporosis, and tumors. This study investigates the genetic basis of a Chinese patient clinically diagnosed with presumed Werner syndrome and partial lipoatrophic diabetes mellitus.High-throughput sequencing of genomic DNA from a blood sample was conducted. Confirmation of the identified homozygous variant (WRN_intron9 c.1270-1G>C) involved the construction of a mutant overexpression vector, primer design, PCR amplification, and sequencing. In silico predictions and structural modeling assessed the variant's pathogenicity, while cell function assays validated the induced phenotype.The study identifies a novel WRN variant as a potential pathogenic factor in the patient. This variant co-segregated with the disease in the pedigree. Database searches (Human Gene Mutation Database, Leiden Open Variant Database, UMD-DMD) revealed its novelty. Simulation predicts exon 10 tandem repeat escape due to the WRN_intron9 c.1270-1G>C mutation. Cellular assays confirm senescent phenotype induction and progerin accumulation, leading to premature cellular senescence.The study reports the identification of a novel WRN variant, likely the pathogenic basis for Werner Syndrome in the Chinese patient. Notably, this marks the first report of a homozygous WRN variant in Werner Syndrome.

ORGANISM(S): Mus musculus

PROVIDER: GSE269189 | GEO | 2024/08/05

REPOSITORIES: GEO

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