Abstract
BackgroundDyskeratosis congenita (DC) is an inherited telomeropathy characterized by mucocutaneous dysplasia, bone marrow failure, cancer predisposition, and other somatic abnormalities. Cells from patients with DC exhibit short telomere. The genetic basis of the majority of DC cases remains unknown.MethodsA 2 generational Chinese Han family with DC was studied using targeted capture and next-generation sequencing to identify the underlying DC-related mutations.ResultsIn this study, we identified a unique homozygous WD repeat containing antisense to TP53 (WRAP53) Arg298Trp mutation in the proband with DC and heterozygous WRAP53 Arg298Trp mutations in his asymptomatic, consanguineous parents and his sister, indicating an autosomal recessive inheritance mode. The proband with the homozygous WRAP53 Arg298Trp mutation had short telomere, classic clinical symptoms, and no response to danazol, glucocorticoid or cyclosporin A.ConclusionsThus, we reported for the first time that a unique homozygous WRAP53 mutation site underlies the development of DC.
Highlights
Dyskeratosis congenita (DC) is an inherited telomeropathy characterized by ectodermal dysplasia, bone marrow failure (BMF), cancer predisposition and other somatic abnormalities
We identified a unique homozygous DCassociated WARP53 Arg298Trp mutation with an autosomal recessive inheritance mode in a DC patient who was an offspring of a consanguineous marriage
Clinical findings The proband (IV-1) was a 30-year-old Han Chinese male who was born in a rural village in Sichuan Province, China, and who was the second child of consanguineous parents with no family history of BMF
Summary
Dyskeratosis congenita (DC) is an inherited telomeropathy characterized by mucocutaneous dysplasia, bone marrow failure, cancer predisposition, and other somatic abnormalities. The genetic basis of the majority of DC cases remains unknown. Dyskeratosis congenita (DC) is an inherited telomeropathy characterized by ectodermal dysplasia, bone marrow failure (BMF), cancer predisposition and other somatic abnormalities. 2 unrelated DC patients with autosomal recessive inheritance [21]; that study was the only report far of WRAP53 mutations in DC. The two unrelated probands presented the classical triad of skin pigmentation, oral leukoplakia, and nail dysplasia, and the peripheral lymphocytes of the probands had shortening telomere lengths. Parents and siblings of the probands harbored heterozygous WRAP53 mutations and had normal telomere lengths, showing that it was an autosomal recessive inheritance [21]. Knockdown of WRAP53 causes the loss of TERC and dyskerin from the Cajal bodies, mislocalization of TERC in the nucleolus, and progressive telomere shortening [21, 22]
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