Ataxia and pancytopenia caused by a mutation in TINF2

Tsangaris, Elena; Adams, Sally-Lin; Yoon, Grace; Chitayat, David; Lansdorp, Peter M.; Dokal, Inderjeet; Dror, Yigal

doi:10.1007/s00439-008-0576-7

Cited by 29 publications

(23 citation statements)

References 25 publications

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“…In addition to DC, mutations of TINF2 were also identified in patients with other diseases associated with bone marrow failure (e.g. ataxia-pancytopenia and aplastic anemia) (6,21,22).…”

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confidence: 99%

TIN2 Protein Dyskeratosis Congenita Missense Mutants Are Defective in Association with Telomerase

Yang

Kim

et al. 2011

Journal of Biological Chemistry

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Dyskeratosis congenita (DC) is a progressive and heterogeneous congenital disorder that affects multiple systems and is characterized by bone marrow failure and a triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. One common feature for all DC patients is abnormally short telomeres and defects in telomere biology. Most of the known DC mutations have been found to affect core components of the telomerase holoenzyme. Recently, multiple mutations in the gene encoding the telomeric protein TIN2 have been identified in DC patients with intact telomerase genes, but the molecular mechanisms underlying TIN2 mutation-mediated DC remain unknown. Here, we demonstrate that ectopic expression of TIN2 with DC missense mutations in human cells led to accelerated telomere shortening, similar to the telomere phenotypes found in DC patients. However, this telomere shortening was not accompanied by changes in total telomerase activity, localization of TIN2, or telomere end protection status. Interestingly, we found TIN2 to participate in the TPP1-dependent recruitment of telomerase activity. Furthermore, DC mutations in TIN2 led to its decreased ability to associate with TERC and telomerase activity. Taken together, our data suggest that TIN2 mutations in DC may compromise the telomere recruitment of telomerase, leading to telomere shortening and the associated pathogenesis.

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“…In addition to DC, mutations of TINF2 were also identified in patients with other diseases associated with bone marrow failure (e.g. ataxia-pancytopenia and aplastic anemia) (6,21,22).…”

mentioning

confidence: 99%

TIN2 Protein Dyskeratosis Congenita Missense Mutants Are Defective in Association with Telomerase

Yang

Kim

et al. 2011

Journal of Biological Chemistry

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“…These facts suggested that TGM6 may be a pathogenic factor for both familial AML and SCA; and there have been numerous reports of mutations of one gene causing a disease with a wide range of symptoms including ataxia and blood malignancies, such as ATM mutations causing ataxiatelangiectasia, 27 and TERC/TERT mutations causing dyskeratosis congenital. 28 In fact, two members of TGM family, TGM2 and FXIII-A, 16 have been recognised as pleiotropy genes and can affect multiple traits. So we suggest that TGM6 may be another pleiotropy gene, and contribute to both ataxia and leukaemia.…”

Section: Discussionmentioning

confidence: 99%

Positional cloning and next-generation sequencing identified a TGM6 mutation in a large Chinese pedigree with acute myeloid leukaemia

et al. 2014

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An inherited predisposition to acute myeloid leukaemia (AML) is exceedingly rare, but the investigation of these families will aid in the delineation of the underlying mechanisms of the more common, sporadic cases. Three AML predisposition genes, RUNX1, CEBPA and GATA2, have been recognised, but the culprit genes in the majority of AML pedigrees remain obscure. We applied a combined strategy of linkage analysis and next-generation sequencing (NGS) technology in an autosomal-dominant AML Chinese family with 11 cases in four generations. A genome-wide linkage scan using a 500K SNP genotyping array was conducted to identify a previously unreported candidate region on 20p13 with a maximum multipoint heterogeneity LOD (HLOD) score of 3.56 (P ¼ 0.00005). Targeted NGS within this region and whole-exome sequencing (WES) revealed a missense mutation in TGM6 (RefSeq, NM_198994.2:c.1550T4G, p.(L517W)), which cosegregated with the phenotype in this family, and was absent in 530 healthy controls. The mutated amino acid was located in a highly conserved position, which may be deleterious and affect the activation of TGM6. Our results strongly support the candidacy of TGM6 as a novel familial AML-associated gene.

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“…(187) Telomeropathies, a disorder caused by defects in the telomere maintenance machinery, just recently discovered shared a constellation of overlapping syndromes. (188,189) DKC was the first disorder associated to telomerophaty, manifest the diagnostic triad of oral leukoplakia, skin hyperpigmentation, nail dystrophy (190)(191)(192), most prominent display organ failure, usually in the bone marrow and a seri of symptoms that less frequently appear such as aplastic anemia or specific lymphopenias. (193,194) In adulthood, idiopathic pulmonary fibrosis (IPF) is the most common symptom of a telomeropathy.…”

Section: Telomeres and Diseasesmentioning

confidence: 99%

Telomere in Aging and Age-Related Diseases

2017

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B ACKGROUND:The number of elderly population in the world keep increasing. In their advanced ages, many elderly face years of disability because of multiple chronic diseases, frailty, making them lost their independence. Consequently, this could have impacts on social and economic stability. A huge challenge has been sent for biomedical researchers to compress or at least eliminate this period of disability and increase the health span. CONTENT:Over the past decades, many studies of telomere biology have demonstrated that telomeres and telomere-associated proteins are implicated in human diseases. Accelerated telomere erosion was clearly correlated with a pack of metabolic and inflammatory diseases. Critically short telomeres or the unprotected end, are likely to form telomeric fusion, generating genomic Abstract R E V I E W A R T I C L Einstability, the cornerstone for carcinogenesis. Enlightening how telomeres involved in the mechanisms underlying the diseases' pathogenesis was expected to uncover new molecular targets for any important diagnosis or therapeutic implications. SUMMARY:Telomere shortening was foreseen as an imporant mechanism to supress tumor by limiting cellular proliferative capacity by regulating senescence check point activation. Many human diseases and carcinogenesis are causally related to defective telomeres, asserting the importance of telomeres sustainment. Thus, telomere length assessment might serve as an important tool for clinical prognostic, diagnostic, monitoring and management.

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Ataxia and pancytopenia caused by a mutation in TINF2

Cited by 29 publications

References 25 publications

TIN2 Protein Dyskeratosis Congenita Missense Mutants Are Defective in Association with Telomerase

TIN2 Protein Dyskeratosis Congenita Missense Mutants Are Defective in Association with Telomerase

Positional cloning and next-generation sequencing identified a TGM6 mutation in a large Chinese pedigree with acute myeloid leukaemia

Telomere in Aging and Age-Related Diseases

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