A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.
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...
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Public Library of Science (PLoS)
2013-08-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003695&type=printable |
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| author | Bari J Ballew Vijai Joseph Saurav De Grzegorz Sarek Jean-Baptiste Vannier Travis Stracker Kasmintan A Schrader Trudy N Small Richard O'Reilly Chris Manschreck Megan M Harlan Fleischut Liying Zhang John Sullivan Kelly Stratton Meredith Yeager Kevin Jacobs Neelam Giri Blanche P Alter Joseph Boland Laurie Burdett Kenneth Offit Simon J Boulton Sharon A Savage John H J Petrini |
| author_facet | Bari J Ballew Vijai Joseph Saurav De Grzegorz Sarek Jean-Baptiste Vannier Travis Stracker Kasmintan A Schrader Trudy N Small Richard O'Reilly Chris Manschreck Megan M Harlan Fleischut Liying Zhang John Sullivan Kelly Stratton Meredith Yeager Kevin Jacobs Neelam Giri Blanche P Alter Joseph Boland Laurie Burdett Kenneth Offit Simon J Boulton Sharon A Savage John H J Petrini |
| author_sort | Bari J Ballew |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8227b26c0dbc4b9aa78d97185bee92cb |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2013-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-8227b26c0dbc4b9aa78d97185bee92cb2025-08-20T02:22:49ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-08-0198e100369510.1371/journal.pgen.1003695A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.Bari J BallewVijai JosephSaurav DeGrzegorz SarekJean-Baptiste VannierTravis StrackerKasmintan A SchraderTrudy N SmallRichard O'ReillyChris ManschreckMegan M Harlan FleischutLiying ZhangJohn SullivanKelly StrattonMeredith YeagerKevin JacobsNeelam GiriBlanche P AlterJoseph BolandLaurie BurdettKenneth OffitSimon J BoultonSharon A SavageJohn H J PetriniDyskeratosis 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003695&type=printable |
| spellingShingle | Bari J Ballew Vijai Joseph Saurav De Grzegorz Sarek Jean-Baptiste Vannier Travis Stracker Kasmintan A Schrader Trudy N Small Richard O'Reilly Chris Manschreck Megan M Harlan Fleischut Liying Zhang John Sullivan Kelly Stratton Meredith Yeager Kevin Jacobs Neelam Giri Blanche P Alter Joseph Boland Laurie Burdett Kenneth Offit Simon J Boulton Sharon A Savage John H J Petrini A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLoS Genetics |
| title | A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. |
| title_full | A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. |
| title_fullStr | A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. |
| title_full_unstemmed | A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. |
| title_short | A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. |
| title_sort | recessive founder mutation in regulator of telomere elongation helicase 1 rtel1 underlies severe immunodeficiency and features of hoyeraal hreidarsson syndrome |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003695&type=printable |
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