Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood

Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Clinical Genetics (Impact Factor: 3.93). 02/2011; 81(5):470-8. DOI: 10.1111/j.1399-0004.2011.01658.x
Source: PubMed


Sasa GS, Ribes-Zamora A, Nelson ND, Bertuch AA. Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood.
Dyskeratosis congenita (DC) is a telomere biology disorder characterized by a mucocutaneous triad, aplastic anemia, and predisposition to cancer. Mutations in a narrow segment of TINF2 exon 6 have been recognized to cause often-severe DC that is either sporadic or autosomal dominant. We describe three children with very early presentations of DC, including one with the severe variant known as Revesz syndrome. Although most TINF2 mutations reported to date are missense changes, each of our patients carried a novel heterozygous nonsense or frameshift mutation, revealing a new 5′ boundary to the affected gene segment in patients with DC. Examination of patient-derived lymphoblastoid cell lines revealed stable expression of the predicted truncated TIN2 proteins. In co-immunoprecipitation assays, the ability of a truncation mutant to interact with TRF1 was severely impaired, whereas the ability of the most common DC-associated mutant was much less affected. This suggests that the disruption of TIN2–TRF1 interaction may contribute to the severe clinical phenotype observed in the context of the TIN2 truncation mutation, but is unlikely to be the primary cause of telomere shortening associated with the more prevalent TIN2 missense mutations. Telomere flow-fluorescent in situ hybridization (FISH) analysis of one pedigree showed the dramatic effect a de novo nonsense TINF2 mutation had on telomere length in early development. These cases underscore the severe manifestations of truncating TINF2 mutations.

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    • "This model and the heterogeneity in environmental exposures could explain the highly variable age of onset of IPF in cohorts with telomeropathies. Environmental insult-driven accelerated telomere shortening may also explain why the diagnostic triad symptoms of DKC may appear at widely varying ages, both before and after bone marrow failure (Vulliamy et al., 2002; Yamaguchi et al., 2005; Savage et al., 2008; Tsangaris et al., 2008; Walne et al., 2008; Sasa et al., 2012), and in some cases fail to appear at all. Heterogeneity in environmental exposures could provoke tissue failure asynchronously, resulting in a unique order of symptom onset for each patient. "
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    The Journal of Cell Biology 05/2014; 205(3):289-99. DOI:10.1083/jcb.201401012 · 9.83 Impact Factor
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    • "For instance, progressive telomere shortening is directly implicated in replicative senescence, and reactivation of the telomerase represents one of the hallmarks of cancer cells (Shay & Wright, 2011). In addition, mutation and dysfunction of telomerase complex components (e.g., dyskerin) and telosome/shelterin subunits (e.g., TIN2) have been identified in diseases with premature aging phenotypes and predisposition to cancer (Heiss et al., 1998; Savage et al., 2008; Vulliamy et al., 2008; Walne et al., 2008; Zhong et al., 2011; Sasa et al., 2012). "
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    Aging cell 07/2013; 12(6). DOI:10.1111/acel.12137 · 6.34 Impact Factor
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    • "Findings included pancolitis and atrophic mucosa, and pathology showed gland dropout, lamina propria fibrosis, intraepithelial lymphocytosis, and apoptosis, similar to one of our index cases. Esophageal stenosis preceded or followed lower GI disease at times (Berezin et al., 1996; Knight et al., 1999; Arca et al., 2003; Sznajer et al., 2003; Sasa et al., 2012). Intestinal disease presented earlier in HH than DC (mean 1.4 vs. 17 years, respectively). "
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    ABSTRACT: Defects in telomere maintenance genes cause pathological telomere shortening, and manifest in syndromes which have prominent phenotypes in tissues of high turnover: the skin and bone marrow. Because the gastrointestinal (GI) epithelium has rapid turnover, we sought to determine whether telomere syndromes cause GI disease, and to define its prevalence, spectrum and natural history. We queried subjects in the Johns Hopkins Telomere Syndrome Registry for evidence of luminal GI disease. In sixteen percent of Registry subjects (6 of 38), there was a history of significant GI pathology, and 43 additional cases were identified in the literature. Esophageal stenosis, enteropathy and enterocolitis were the recurrent findings. In the intestinal mucosa, there was striking villous atrophy, extensive apoptosis, and anaphase bridging pointing to regenerative defects in the epithelial compartment. GI disease was often the first and most severe manifestation of telomere disease in young children. These findings indicate that telomere dysfunction disrupts the epithelial integrity in the human GI tract manifesting in recognizable disease processes. A high index of suspicion should facilitate diagnosis and management. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
    Aging cell 12/2012; 12(2). DOI:10.1111/acel.12041 · 6.34 Impact Factor
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