Open AccessA Recessive Founder Mutation in Regulator of Telomere Elongation Helicase 1, RTEL1, Underlies Severe Immunodeficiency and Features of Hoyeraal Hreidarsson Syndrome
Author(s) -
Bari J. Ballew,
Joseph Vijai,
Saurav De,
Grzegorz Sarek,
Jean Baptiste Vannier,
Travis H. 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 B. Jacobs,
Neelam Giri,
Blanche P. Alter,
Joseph F. Boland,
Laurie Burdett,
Kenneth Offit,
Simon J. Boulton,
Sharon A. Savage,
John H.J. Petrini
Publication year - 2013
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1003695
Subject(s) - biology , dyskeratosis congenita , genetics , mutation , immunodeficiency , germline mutation , telomere , gene , immune system
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 .