TINF2 – Dyskeratosis congenita

TINF2 encodes a core component of the shelterin telomere‐protection complex, which binds TRF1 and TRF2 to maintain telomere integrity. Dyskeratosis congenita (DC) is a rare, multisystem bone marrow failure syndrome characterized by very short telomeres, mucocutaneous abnormalities, aplastic anemia, and cancer predisposition. Initially, ~60% of DC patients lacked mutations in known telomerase genes, prompting linkage studies that implicated TINF2 on chromosome 14q11.2.

Genetic analyses in an autosomal dominant DC pedigree revealed heterozygous missense mutations K280E, R282H, and R282S segregating with disease in five affected relatives (autosomal dominant segregation) and in three additional unrelated probands, establishing TINF2 as the fifth DC gene (6 affected relatives)[PMID:18252230]. Subsequent screening of 175 DC patients identified TINF2 mutations in 33 index cases (~19% of uncharacterized DC), including recurrent variants at codon 282 (Arg→His or Cys), often arising de novo, and frameshift or nonsense truncations in exon 6 (33 probands)[PMID:18669893].

The variant spectrum comprises predominantly missense changes targeting codon 282 (e.g., c.844C>T (p.Arg282Cys)), alongside rare truncating alleles such as c.811C>T (p.Gln271Ter) and c.839del (p.Lys280fs). Both recurrent and unique variants account for severe early‐onset DC and its Revesz syndrome variant, with phenotypic variability including pulmonary fibrosis, liver angiosarcoma, and immune dysregulation.

Clinically, TINF2‐mutant DC presents with the classical triad of nail dystrophy (HP:0008404), oral leukoplakia (HP:0002745), and abnormal skin pigmentation (HP:0001000), often accompanied by bone marrow failure in childhood. Extra‐hematopoietic manifestations include pulmonary fibrosis post‐HSCT, liver vascular pathology, and neurologic complications, underscoring the need for multidisciplinary monitoring.

Functional studies demonstrate that truncating TIN2 mutants show impaired TRF1 binding in co‐immunoprecipitation assays and that patient lymphoblastoid cells exhibit markedly shortened telomeres by flow‐FISH. Telomere length measurement distinguishes pathogenic from benign TINF2 variants, and CRISPR‐mediated disruption of mutant alleles rescues telomere length and stem cell proliferative capacity in human ESCs and HSPCs (rescue by exon 2 editing)[PMID:21477109; PMID:35421215].

Taken together, abundant genetic and experimental data yield a definitive gene–disease relationship for TINF2 in DC. Identification of TINF2 mutations informs diagnostic telomere length testing, guides HSCT conditioning and monitoring for organ toxicities, and supports exploration of gene‐editing therapies. Key take‐home: Heterozygous TINF2 mutations cause autosomal dominant DC via shelterin dysfunction and critically short telomeres, with direct implications for diagnosis, surveillance, and therapeutic development.

References

• American journal of human genetics • 2008 • TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita PMID:18252230
• Blood • 2008 • TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes PMID:18669893
• Clinical genetics • 2012 • Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood PMID:21477109
• Blood • 2022 • Editing TINF2 as a potential therapeutic approach to restore telomere length in dyskeratosis congenita PMID:35421215

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