TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes - PubMed (original) (raw)

Amanda J Walne et al. Blood. 2008.

Abstract

Dyskeratosis congenita (DC) is a multisystem bone marrow failure syndrome characterized by a triad of mucocutaneous abnormalities and a predisposition to cancer. The genetic basis of DC remains unknown in more than 60% of patients. Mutations have been identified in components of the telomerase complex (dyskerin, TERC, TERT, NOP10, and NHP2), and recently in one component of the shelterin complex TIN2 (gene TINF2). To establish the role of TINF2 mutations, we screened DNA from 175 uncharacterised patients with DC as well as 244 patients with other bone marrow failure disorders. Heterozygous coding mutations were found in 33 of 175 previously uncharacterized DC index patients and 3 of 244 other patients. A total of 21 of the mutations affected amino acid 282, changing arginine to histidine (n = 14) or cysteine (n = 7). A total of 32 of 33 patients with DC with TINF2 mutations have severe disease, with most developing aplastic anaemia by the age of 10 years. Telomere lengths in patients with TINF2 mutations were the shortest compared with other DC subtypes, but TERC levels were normal. In this large series, TINF2 mutations account for approximately 11% of all DC, but they do not play a significant role in patients with related disorders. This study emphasises the role of defective telomere maintenance on human disease.

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Figures

Figure 1

Figure 1

Conservation of amino acids in a small region of TIN2 between different species. Close-up of the residues mutated in the patients with DC. Arrows indicate the sites of mutations. Changes are K280X (n = 2), R282C (n = 7), R282H (n = 14), P283A, P283H, P283S, T284A, T284Hfs8X, L287P, P289S, F290LfsX2, R291G, and Q298RfsX19. Red indicates highly conserved; blue, limited conservation; black, no conservation. Alignment obtained using MultAlin.

Figure 2

Figure 2

Telomere lengths in patients with DC with TINF2 mutations are the shortest compared with other DC subtypes. (A) Telomere lengths in healthy controls (○, n = 112), patients (♦, n = 16) and parents (formula image, n = 15). (B) Telomere length compassion between DC patients with TINF2 mutations (♦, n = 16), DKC1 mutations (formula image, n = 67) and healthy controls (○, n = 112). The line of best fit for the healthy controls is shown in panels A and B. (C) Comparison of age-adjusted delta Tel in healthy controls and patients with DKC1 and TINF2 mutations. The box represents the interquartile range which contains the 50% of values. The whiskers are lines that extend from the box to the highest and lowest values, excluding outliers and extreme outliers (○ and formula image, respectively). A line across the box indicates the median.

Figure 3

Figure 3

TERC/ABL levels are not reduced in patients with DC with TINF2 mutations. Comparison of TERC/ABL levels between healthy controls (n = 24), patients with DC with TINF2 mutations (n = 5), and patients with DC with DKC1 mutations (n = 26). The P value between TERC/ABL levels for TINF2 and DKC1 patients is given. The box represents the interquartile range which contains the 50% of values. The whiskers are lines that extend from the box to the highest and lowest values, excluding outliers (△). A line across the box indicates the median.

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