Alt. symbols: TIN2

Approved name: TERF1 interacting nuclear factor 2
Alt. names: TERF1 (TRF1)-interacting nuclear factor 2

Location: 14q12: 24238286 - 24242663 (-)
Gene type: protein_coding, 33 transcripts.

Scores: LoFtool: 0.146000 | pLI: 0.15855436 | LOEUF: 0.671

HGNC: 11824

NCBI: 26277, RefSeq: NG_016650.1

Ensembl: ENSG00000092330.19

LRG_342 | Status: public

OMIM: 604319

Expression | ProteinAtlas

TINF2 encodes a member of the shelterin complex, which protects telomere ends and cooperates with telomerase to maintain telomeres. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. TINF2 plays a central role in shelterin assembly and function by connecting double-stranded DNA-binding proteins TRF1 and TRF2 to the single-stranded DNA-binding unit TPP1/POT1. Isoform 1 (UniProt Q9BSI4-1) has also been suggested to play additional roles in tethering telomeres to the nuclear matrix.

Monoallelic frameshift, nonsense and missense mutations in TINF2 have been associated with autosomal dominant dyskeratosis congenita (DKC) [MIM:613990] and Revesz syndrome [MIM:268130]. DKC is an inherited bone marrow failure syndrome classically characterized by the triad of mucosal leukoplakia, nail dysplasia, and abnormal skin pigmentation. Affected individuals are at increased risk for the development of aplastic anemia and malignancy. Less common features include epiphora, premature gray ha ir, microcephaly, developmental delay, and pulmonary fibrosis, among others. Though the clinical phenotype along the DKC continuum of disorders may be highly variable, all affected individuals have shortened telomeres due to a defect in telomere maintenance. Revesz syndrome is considered to be a severe, infantile onset condition on the DKC spectrum, featuring bilateral exudative retinopathy, developmental delay, cerebellar hypoplasia, severe bone marrow failure and very short telomere lengths in addition to the classic DKC triad. The immunologic features of telomere dysfunction syndromes remain underappreciated despite being significant potential contributors to early morbidity and mortality; thus far, there is clear evidence for an immunodeficiency phenotype, but autoimmunity has yet to be described. Knudson et al. (2005) described the immunologic phenotypes of 10 members of a large 3-generation family with an autosomal dominant DKC due to a TERC mutation. They found severe B lymphopenia, decreased IgM levels, moderately reduced T cell number, reduced lymphocyte proliferation and increased lymphocyte apoptosis. The degree of telomere shortening appeared to correspond to in vivo and in vitro immune findings. Jyonouchi et al. (2011) examined the immunophenotype of 7 pediatric DKC patients and found that lymphopenia, low B-cell count, hypogammaglobulinemia, and decreased T-cell function were the most frequent laboratory abnormalities on initial presentation, preceding the development of significant anemia or thrombocytopenia (PMID: 27088026). Recurrent sinopulmonary or opportunistic infections, as well as severe enteropathy were also described (PMID: 21284747). Hoffman et al. (2016) reported a heterozygous TINF2 variant (S245Y) in a previously healthy 52 year old woman presenting only with idiopathic pulmonary fibrosis and panhypogammaglobulinemia (PMID: 27088026). Though this variant has historically been controversial because patients show normal telomere lengths in peripheral blood cells but present with DKC-associated clinical phenotypes, this further drew attention to hypogammaglobulinemia as a potential manifestation of telomere syndromes. Missense mutations in TINF2 tend to cluster in a hot-spot (aa270-300) immediately C-terminal to the TRF1-binding domain. [Load More]