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.
"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. "
[Show abstract][Hide abstract] ABSTRACT: A constellation of related genetic diseases are caused by defects in the telomere maintenance machinery. These disorders, often referred to as telomeropathies, share symptoms and molecular mechanisms, and mounting evidence indicates they are points along a spectrum of disease. Several new causes of these disorders have been recently discovered, and a number of related syndromes may be unrecognized telomeropathies. Progress in the clinical understanding of telomeropathies has in turn driven progress in the basic science of telomere biology. In addition, the pattern of genetic anticipation in some telomeropathies generates thought-provoking questions about the way telomere length impacts the course of these diseases.
The Journal of Cell Biology 05/2014; 205(3):289-99. DOI:10.1083/jcb.201401012 · 9.83 Impact Factor
"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). "
[Show abstract][Hide abstract] ABSTRACT: Telomeres are specialized structures at the ends of eukaryotic chromosomes that are important for maintaining genome stability and integrity. Telomere dysfunction has been linked to aging and cancer development. In mammalian cells, extensive studies have been carried out to illustrate how core telomeric proteins assemble on telomeres to recruit the telomerase and additional factors for telomere maintenance and protection. In comparison, how changes in growth signaling pathways impact telomeres and telomere-binding proteins remains largely unexplored. The phosphatidylinositol 3-kinase (PI3-K)/Akt (also known as PKB) pathway, one of the best characterized growth signaling cascades, regulates a variety of cellular function including cell proliferation, survival, metabolism, and DNA repair, and dysregulation of PI3-K/Akt signaling has been linked to aging and diseases such as cancer and diabetes. In this study, we provide evidence that the Akt signaling pathway plays an important role in telomere protection. Akt inhibition either by chemical inhibitors or small interfering RNAs induced telomere dysfunction. Furthermore, we found that TPP1 could homodimerize through its OB fold, a process that was dependent on the Akt kinase. Telomere damage and reduced TPP1 dimerization as a result of Akt inhibition was also accompanied by diminished recruitment of TPP1 and POT1 to the telomeres. Our findings highlight a previously unknown link between Akt signaling and telomere protection. This article is protected by copyright. All rights reserved.
"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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