Alt. symbols: Ptop | Pip1 | Tpp1 | Tint1

Approved name: ACD shelterin complex subunit and telomerase recruitment factor
Alt. names: adrenocortical dysplasia homolog (mouse) | TIN2 interacting protein 1, POT1 and TIN2 organizing protein

Location: 16q22.1: 67657512 - 67660810 (-)
Gene type: protein_coding, 44 transcripts.

Scores: LoFtool: 0.872000 | pLI: 0.00000058 | LOEUF: 1.187

HGNC: 25070

NCBI: 65057, RefSeq: NG_042874.1

Ensembl: ENSG00000102977.18

LRG_1237 | Status: public

OMIM: 609377

Expression | ProteinAtlas

This gene encodes adrenocortical dysplasia protein homolog (aka TPP1), a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length by facilitating the replication of the double-stranded telomeric DNA tracts and protects telomere ends from unregulated DNA repair activities. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. 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. Promotes binding of POT1 to single-stranded telomeric DNA. Modulates the inhibitory effects of POT1 on telomere elongation. The ACD-POT1 heterodimer enhances telomere elongation by recruiting telomerase to telomeres and increasing its processivity. May play a role in organogenesis. Although TPP1 was originally described as a bridging factor between TRF1 and TRF2, which participate in a pathway with POT1 as a negative regulator of telomerase-dependent telomere length control, more recent studies suggest that TPP1 could directly promote telomerase activity at the telomere. A part of the TPP1 oligonucleotide/oligosaccharide-binding (OB) fold named TEL patch that interacts with the catalytic subunit of telomerase, hTERT, has been proven essential for telomerase activation. TPP1 has also been demonstrated as the only pathway required for recruitment of telomerase to chromosome ends, and it also defines telomere length homeostasis in hESCs.

Mutations in this gene have apparently been reported only in 2 families so far (PMID:25233904, PMID:25205116). The index patient of the family reported by Kocak, H. in 2014 (PMID:25233904) was diagnosed with Hoyeraal-Hreidarsson syndrome, a severe form of dyskeratosis congenita. The proband inherited the p.K170del mutation from his father and the p.P491T mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. The proband's twin sibling died at age 3mo fr om pneumonia and was not available for testing. Characterization of the mutations revealed that the K170 deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 did not seem as deleterious to TPP1 function. Carriers of the p.K170del allele (father and one sister) were considered unaffected but showed telomere length below the first percentile. The father had gray hair starting at age 16 yr, diffuse white lichenoid striae in gingiva, and short roots for some teeth; while the sister was diagnosed with Attention deficit hyperactivity disorder and Tourette's syndrome. Telomere length of the mother was between the 10%-50% percentile and did not show clinical manifestations. Also in 2014, Guo Y. et. al (PMID:25205116) reported a 6-generation family with a history of hematopoietic conditions such as aplastic anemia, pernicious anemia, bone marrow failure or leukemia. The authors found that the same heterozygous p.K170del mutation (found in the other family) was segregating with disease in this family (3 affected carriers, 2 unaffected non-carriers, 3 affected and 3 unaffected were not tested). All three affected carriers showed reduced telomere length. HEK cells overexpressing the K170del mutation showed that TPP1 was able to localize to telomeres but failed to recruit telomerase to telomeres.There are currently 64 reported variants in ClinVar: 59 VUS (including 2 frameshift and 1 nonsense mutations), 1 pathogenic (1 frameshift), 1 Likely Benign and 2 Benign, and 1 with conflicting classification. [Load More]