TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes

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.

Allo-SCT in a patient with CRMCC with aplastic anemia using a reduced intensity conditioning regimen

“…Savage et al 7 described a case of CRMCC who died after BMT; however, detailed information on the conditioning regimen was not available. Walne et al 8 also described four cases of CRMCC with a TINF2 mutation, of which one received BMT, but details on the conditioning regimen and transplantation courses were not reported. In DKC, circulating lymphocytes and fibroblasts exhibit an increased in vitro sensitivity to radiation and alkylating agents.…”

“…7 Mutated amino acids were tightly clustered in the position between 280 and 290 in classic DKC or CRMCC patients. 7,8 On the basis of these findings, a diagnosis of CRMCC was made. At the age of 17 months, the exudative retinopathy was successfully treated with laser coagulation, pars plana vitrectomy and the intra-vitreal administration of vascular endothelial growth factor inhibitors.…”

“…We found two previous reports of CRMCC patients with an identical mutation in TINF2 to that in our patient. 7,8 Kajtar et al 4 described a 2-year-old girl with CRMCC successfully treated with allogeneic BMT from an HLA-identical brother. The post-transplantation course in this patient was uneventful with only mild GVHD.…”

TCAB1: Driving telomerase to Cajal bodies

“…11,12 Autosomal dominant forms of DC are caused by mutations in TERT, TERC or the telomere binding protein TIN2, providing a clear link between telomere shortening and the pathophysiology of DC. [13][14][15][16] Several dedicated cofactors associate with dyskerin and are required for telomerase RNP assembly and function. Many of these, such as NAF1, pontin and reptin, aid in RNP assembly but do not remain associated with the mature telomerase enzyme.…”

Dyskeratosis congenita

“…More than 30 such cases have been described, and recent studies showed that patients with HH have very short telomeres. Several patients with HH have now been found to have mutations in DC genes proven to cause DC, including DKC1, TINF2, or TERT [16][17][18].…”