Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita
Hemanth Tummala, … , Thomas Vulliamy, Inderjeet Dokal
Hemanth Tummala, … , Thomas Vulliamy, Inderjeet Dokal
Published May 1, 2015; First published April 20, 2015
Citation Information: J Clin Invest. 2015;125(5):2151-2160. https://doi.org/10.1172/JCI78963.
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Categories: Research Article Aging Genetics Hematology

Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita

Abstract

Dyskeratosis congenita (DC) and related syndromes are inherited, life-threatening bone marrow (BM) failure disorders, and approximately 40% of cases are currently uncharacterized at the genetic level. Here, using whole exome sequencing (WES), we have identified biallelic mutations in the gene encoding poly(A)-specific ribonuclease (PARN) in 3 families with individuals exhibiting severe DC. PARN is an extensively characterized exonuclease with deadenylation activity that controls mRNA stability in part and therefore regulates expression of a large number of genes. The DC-associated mutations identified affect key domains within the protein, and evaluation of patient cells revealed reduced deadenylation activity. This deadenylation deficiency caused an early DNA damage response in terms of nuclear p53 regulation, cell-cycle arrest, and reduced cell viability upon UV treatment. Individuals with biallelic PARN mutations and PARN-depleted cells exhibited reduced RNA levels for several key genes that are associated with telomere biology, specifically TERC, DKC1, RTEL1, and TERF1. Moreover, PARN-deficient cells also possessed critically short telomeres. Collectively, these results identify a role for PARN in telomere maintenance and demonstrate that it is a disease-causing gene in a subset of patients with severe DC.

Authors

Hemanth Tummala, Amanda Walne, Laura Collopy, Shirleny Cardoso, Josu de la Fuente, Sarah Lawson, James Powell, Nicola Cooper, Alison Foster, Shehla Mohammed, Vincent Plagnol, Thomas Vulliamy, Inderjeet Dokal

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Figure 1

Identification of biallelic mutations in PARN.

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Identification of biallelic mutations in PARN. (A–C) Sanger sequencing t...
(A–C) Sanger sequencing traces confirm the presence of the mutations identified by exome sequencing in cases 1-4. Pedigrees are also shown. A representative trace of the variant is shown for parents and cases. The gray shading of the parents in DCR373 indicates that they are predicted to be heterozygous. (D–G) Photographs of case 3 showing some of the clinical features: (D) abnormal dentition and abnormal facial features, including dysmorphic ears and microcephaly; (E) sparse hair, (F and G) nail dystrophy. (H) A linear diagram of the PARN protein shows functional domains and the effect of mutations identified in cases 1-4 giving rise to relevant protein variants. ND1 and ND2, nuclease domain 1 and nuclease domain 2; R3H, conserved arginine and 3-histidine containing domain; RRM, RNA recognition motif; NLS, nuclear localization signal; CTD, C-terminal domain.