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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Published in:PLoS genetics 2013-08, Vol.9 (8), p.e1003695-e1003695
Main Authors: Ballew, Bari J, Joseph, Vijai, De, Saurav, Sarek, Grzegorz, Vannier, Jean-Baptiste, Stracker, Travis, Schrader, Kasmintan A, Small, Trudy N, O'Reilly, Richard, Manschreck, Chris, Harlan Fleischut, Megan M, Zhang, Liying, Sullivan, John, Stratton, Kelly, Yeager, Meredith, Jacobs, Kevin, Giri, Neelam, Alter, Blanche P, Boland, Joseph, Burdett, Laurie, Offit, Kenneth, Boulton, Simon J, Savage, Sharon A, Petrini, John H J
Format: Article
Language:English
Subjects:
Adult
Bone marrow
Deoxyribonucleic acid
DNA
DNA Helicases - genetics
Dyskeratosis Congenita - etiology
Dyskeratosis Congenita - genetics
Dyskeratosis Congenita - pathology
Female
Fetal Growth Retardation - etiology
Fetal Growth Retardation - genetics
Fetal Growth Retardation - pathology
Gene mutations
Genes
Genes, Recessive
Genetic disorders
Germ-Line Mutation
Homozygote
Humans
Immunologic Deficiency Syndromes - genetics
Immunologic Deficiency Syndromes - pathology
Intellectual Disability - etiology
Intellectual Disability - genetics
Intellectual Disability - pathology
Jews
Medical research
Microcephaly - etiology
Microcephaly - genetics
Microcephaly - pathology
Molecular Sequence Data
Mutation
Phenotype
Physiological aspects
Telomerase - genetics
Telomere - genetics
Telomeres
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1003695