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.

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

“…All RTEL1-deficient patients reported so far exhibit abnormally short telomeres, indicating the crucial role of RTEL1 in telomere maintenance. [7][8][9][10][11][12] Accordingly, the telomere length determined by…”

“…1,[4][5][6] Other researchers and we recently reported patients with HH carrying mutations in RTEL1, a gene encoding a DNA helicase. [7][8][9][10][11][12] RTEL1 belongs to a family of iron-sulfur-clustercontaining DNA helicases; other members include XPD, FANCJ, and DDX11/ChlR1. 13 The helicase domain of RTEL1 exerts an in vitro antirecombinogenic activity by displacing DNA recombination intermediates, the so-called D-loop.…”

“…18 Likewise, RTEL1 is important to cope with replicative stress and to repair DNA interstrand crosslinks. 7,18,19 In humans, splice variants generate 2 main RTEL1 isoforms of 1219 amino acids and 1300 amino acids, respectively. 11 The longer RTEL1 isoform possesses an additional RING C4C4 domain at its C-terminal part.…”

RTEL1, une hélicase de l’ADN essentielle à la stabilité du génome

“…Cette proposition semble être confortée par l'observation d'une augmentation des cercles T au cours de la réplication des cellules déficientes en Rtel1 [12] (Figure 2). Dans ce contexte, l'excision de la boucle T semble principalement impliquer le complexe nucléase SLX4 [12,26] (Figure 3) [6,8,9,13,15]. Au total, ces différentes explorations permettent de décrire à ce jour 14 patients atteints de DC/HH porteurs de mutation dans le gène RTEL1.…”

“…Certains de ces facteurs, spécifiquement localisés aux télomères, participent à leur homéosta-sie et leur protection ; d'autres sont nécessaires à la stabilité globale du génome. Plusieurs travaux récents ont permis d'identifier RTEL1 comme un acteur crucial tant pour le maintien des télomères que pour la stabilité du génome dans son ensemble [6][7][8][9][10][11][12][13][14][15][16][17].…”