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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 BJ, Joseph V, De S, Sarek G, Vannier JB, Stracker T, Schrader KA, Small TN, O'Reilly R, Manschreck C, Harlan Fleischut MM, Zhang L, Sullivan J, Stratton K, Yeager M, Jacobs K, Giri N, Alter BP, Boland J, Burdett L, Offit K, Boulton SJ, Savage SA, Petrini JH - PLoS Genet. (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America.

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.

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NCI-318 and MSK-41 pedigrees with RTEL1 mutation and shared risk haplotype.NCI-318 (A) and MSK-41 (B) pedigrees are shown. Red symbols indicate affected individuals. The pink rectangles indicate the shared haplotype between the pedigrees. Each other colored rectangle indicates a unique haplotype.
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pgen-1003695-g001: NCI-318 and MSK-41 pedigrees with RTEL1 mutation and shared risk haplotype.NCI-318 (A) and MSK-41 (B) pedigrees are shown. Red symbols indicate affected individuals. The pink rectangles indicate the shared haplotype between the pedigrees. Each other colored rectangle indicates a unique haplotype.

Mentions: The female proband, NCI-318-1 (family NCI-318) was born prematurely at 32 weeks gestation due to placental clots (Table 1, Figure 1A). Her parents were unrelated and of AJ ancestry. She was small for age and had poor postnatal growth. At 6 months of age she developed recurrent, chronic diarrhea and rectal prolapse. An extensive evaluation for allergic and infectious etiologies was negative. At 11 months of age, a colonoscopy showed severe colitis with evidence of apoptosis in the colonic epithelium. A concurrent immunologic evaluation showed low total B cells (CD 20+) at 14 cells/mm3, NK cells at 65 cells/mm3, and CD8+ T cells were 487 cells/mm3 (normal tenth percentiles are 1,310 cells/mm3, 360 cells/mm3, and 2,100 cells/mm3, respectively [10]), and her mitogen studies were abnormal. Her IgG was low at 26 mg/dL, IgA<5 mg/dL, IgM 29 mg/dL (lower limits of normal for age are 453 mg/dL, 20 mg/dL, and 19 mg/dL, respectively). Chromosome breakage studies were not consistent with Fanconi anemia. Subsequent testing identified peripheral blood telomere length as very short for her age (Figure 2A). An MRI of her brain showed cerebellar hypoplasia. Based on her clinical history and very short telomeres, she was diagnosed with the HH variant of DC. Genetic testing for TERT, TERC, TINF2, NOP10, NHP2, and WRAP53 was negative. She died due to complications following bone marrow transplant at two years of age. The mother and father are both clinically healthy, and their telomeres are normal (30 percentile and 70 percentile for age, respectively) (Figure 2A).


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

Ballew BJ, Joseph V, De S, Sarek G, Vannier JB, Stracker T, Schrader KA, Small TN, O'Reilly R, Manschreck C, Harlan Fleischut MM, Zhang L, Sullivan J, Stratton K, Yeager M, Jacobs K, Giri N, Alter BP, Boland J, Burdett L, Offit K, Boulton SJ, Savage SA, Petrini JH - PLoS Genet. (2013)

NCI-318 and MSK-41 pedigrees with RTEL1 mutation and shared risk haplotype.NCI-318 (A) and MSK-41 (B) pedigrees are shown. Red symbols indicate affected individuals. The pink rectangles indicate the shared haplotype between the pedigrees. Each other colored rectangle indicates a unique haplotype.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3757051&req=5

pgen-1003695-g001: NCI-318 and MSK-41 pedigrees with RTEL1 mutation and shared risk haplotype.NCI-318 (A) and MSK-41 (B) pedigrees are shown. Red symbols indicate affected individuals. The pink rectangles indicate the shared haplotype between the pedigrees. Each other colored rectangle indicates a unique haplotype.
Mentions: The female proband, NCI-318-1 (family NCI-318) was born prematurely at 32 weeks gestation due to placental clots (Table 1, Figure 1A). Her parents were unrelated and of AJ ancestry. She was small for age and had poor postnatal growth. At 6 months of age she developed recurrent, chronic diarrhea and rectal prolapse. An extensive evaluation for allergic and infectious etiologies was negative. At 11 months of age, a colonoscopy showed severe colitis with evidence of apoptosis in the colonic epithelium. A concurrent immunologic evaluation showed low total B cells (CD 20+) at 14 cells/mm3, NK cells at 65 cells/mm3, and CD8+ T cells were 487 cells/mm3 (normal tenth percentiles are 1,310 cells/mm3, 360 cells/mm3, and 2,100 cells/mm3, respectively [10]), and her mitogen studies were abnormal. Her IgG was low at 26 mg/dL, IgA<5 mg/dL, IgM 29 mg/dL (lower limits of normal for age are 453 mg/dL, 20 mg/dL, and 19 mg/dL, respectively). Chromosome breakage studies were not consistent with Fanconi anemia. Subsequent testing identified peripheral blood telomere length as very short for her age (Figure 2A). An MRI of her brain showed cerebellar hypoplasia. Based on her clinical history and very short telomeres, she was diagnosed with the HH variant of DC. Genetic testing for TERT, TERC, TINF2, NOP10, NHP2, and WRAP53 was negative. She died due to complications following bone marrow transplant at two years of age. The mother and father are both clinically healthy, and their telomeres are normal (30 percentile and 70 percentile for age, respectively) (Figure 2A).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America.

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.

Show MeSH
Related in: MedlinePlus