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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 April 20, 2015
Citation Information: J Clin Invest. 2015;125(5):2151-2160. https://doi.org/10.1172/JCI78963.
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Research Article Aging Genetics Hematology

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

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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 4

PARN deficiency effects telomere biology.

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PARN deficiency effects telomere biology.
(A) Cases of PARN deficiency s...
(A) Cases of PARN deficiency show reduced levels of expression of 4 telomere biology genes in blood. The relative expression of each gene, after normalizing to β-actin, is shown. Samples from cases 1-3 were analyzed, (one sample each from cases 1 and 2, and two independent samples from case 3; n = 3 cases) and compared with controls (n = 19). Bars represent the median relative expression ratio (*P < 0.05, **P < 0.01 Mann-Whitney U test). (B) Case 1 LCLs show reduced levels of expression of 4 telomere biology genes. All genes are normalized to β-actin and are expressed relative to the father’s sample. Data represent mean ± SD, n = 3. (C) Following 0, 1, 2, and 4 hours actinomycin D treatment, mRNA half-life (t1/2) calculated as indicated in hours for each gene is determined in GFP and PARN siRNA knockdown samples. Data represent mean ± SEM, n = 2. (D) Reduced dyskerin and TRF1 protein levels in case 1 LCLs and PARN siRNA–treated cells; β-actin is used as a loading control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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