Dataset Information

A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.

ABSTRACT: Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.

SUBMITTER: Ballew BJ

PROVIDER: S-EPMC3757051 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.

Ballew Bari J BJ Joseph Vijai V De Saurav S Sarek Grzegorz G Vannier Jean-Baptiste JB Stracker Travis T Schrader Kasmintan A KA Small Trudy N TN O'Reilly Richard R Manschreck Chris C Harlan Fleischut Megan M MM Zhang Liying L Sullivan John J Stratton Kelly K Yeager Meredith M Jacobs Kevin K Giri Neelam N Alter Blanche P BP Boland Joseph J Burdett Laurie L Offit Kenneth K Boulton Simon J SJ Savage Sharon A SA Petrini John H J JH

PLoS genetics 20130829 8

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomer ...[more]

PMID: 24009516

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Project description:BackgroundEukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR) and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC) and its severe form Hoyeraal-Hreidarsson Syndrome (HHS) are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency.Methodology/principal findingsWe studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3' overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types.Conclusions/significanceAltogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease.

Project description:High altitude pulmonary edema (HAPE) is a paradigm of pulmonary edema. Mutations in regulator of telomere elongation helicase1 (RTEL1) represent an important contributor to risk for pulmonary fibrosis. However, little information is found about the association between RTEL1 and HAPE risk. The present study was undertaken to tentatively explore the potential relation between single-nucleotide polymorphisms (SNPs) in RTEL1 and HAPE risk in Chinese Han population. A total of 265 HAPE patients and 303 healthy controls were included in our case-control study. Four SNPs in RTEL1 were selected and genotyped using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression with adjustment for gender and age. All P values were Bonferroni corrected, and statistical significance was set at P?<?.0025 (.05/20). In allelic model analysis, we found that the allele "G" of rs6089953 and rs6010621 and the allele "A" of rs2297441 were associated with decreased risk of HAPE. In the genetic model analysis, we found that rs6010621, rs6089953, and rs2297441 were relevant to decreased HAPE risk under dominant model (rs6010621: OR?=?0.55; 95% CI?=?0.39-0.78; P?=?.001; rs6089953: OR?=?0.68; 95% CI?=?0.48-0.96; P?=?.027; rs2297441: OR?=?0.63; 95% CI?=?0.45-0.89; P?=?.008, respectively) and additive model (rs6010621: OR?=?0.51; 95% CI?=?0.46-0.81; P?<?.001; rs6089953: OR?=?0.72; 95% CI?=?0.55-0.95; P?=?.022; rs2297441: OR?=?0.73; 95% CI?=?0.57-0.95; P?=?.019, respectively). SNPs rs6010621 remained significant after Bonferroni correction (P?<?.0025). In addition, haplotype "GG, GT, AT" of rs6089953-rs6010621 were detected significantly associated with HAPE risk (P?<?.05), haplotype "GG" remained significant after Bonferroni correction (P?<?.0025). Our findings provide new evidence for the association between SNPs in RTEL1 and a decreased risk HAPE in the Chinese population. The results need further confirmation.

Dataset Information

A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.

Publications

A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.

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