Abstract
Approximately half of all cases of Hoyeraal–Hreidarsson syndrome (HHS), a multisystem disorder characterized by bone marrow failure, developmental defects and very short telomeres, are caused by germline mutations in genes related to telomere biology. However, the varying symptoms and severity of the disease indicate that additional mechanisms are involved. Here, a 3-year-old boy with HHS was found to carry biallelic germline mutations in WRAP53 (WD40 encoding RNA antisense to p53), that altered two highly conserved amino acids (L283F and R398W) in the WD40 scaffold domain of the protein encoded. WRAP53β (also known as TCAB1 or WDR79) is involved in intracellular trafficking of telomerase, Cajal body functions and DNA repair. We found that both mutations cause destabilization, mislocalization and faulty interactions of WRAP53β, defects linked to misfolding by the TRiC chaperonin complex. Consequently, WRAP53β HHS mutants cannot elongate telomeres, maintain Cajal bodies or repair DNA double-strand breaks. These findings provide a molecular explanation for the pathogenesis underlying WRAP53β-associated HHS and highlight the potential contribution of DNA damage and/or defects in Cajal bodies to the early onset and/or severity of this disease.
Highlights
The hereditary disorder dyskeratosis congenita (DC), and its most severe form the Hoyeraal–Hreidarsson syndrome (HHS), are associated with severely shortened telomeres and a variety of clinical symptoms, including bone marrow failure, fibrosis in the lung and liver, developmental defects and cancer, as well as a classical triad of mucocutaneous features[1].Patients with HHS suffer from intrauterine growth retardation, neurological complications and severe immunodeficiency, often resulting in death during childhood[2].A central feature of DC and HHS is defective maintenance of telomeres and mutations in one of 11 genes controlling telomere homeostasis, including DKC1, TERT, RTEL1, PARN, TINF2, TERC, WRAP53, NOP10, NHP2, CTC1, and ACD (TPP1 protein, linked only to HHS), have been detected in ~70% of cases with DC and 50% with HHS3–18
Here, we show for the first time that biallelic mutations in WRAP53 result in HHS
The missense mutations identified (L283F and R398W) are both located in the WD40 scaffolding domain of the WRAP53β protein and affect amino acids that are highly conserved across species
Summary
Patients with HHS suffer from intrauterine growth retardation, neurological complications and severe immunodeficiency, often resulting in death during childhood[2]. A central feature of DC and HHS is defective maintenance of telomeres and mutations in one of 11 genes controlling telomere homeostasis, including DKC1, TERT, RTEL1, PARN, TINF2 (linked to both DC and HHS), TERC, WRAP53, NOP10, NHP2, CTC1 (linked only to DC), and ACD (TPP1 protein, linked only to HHS), have been detected in ~70% of cases with DC and 50% with HHS3–18. Several investigations have revealed that the severity of DC or HHS cannot be explained on the basis of telomere length alone[19]. Patients with mutations in the core components of telomerase
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