Table 1:
Germline genetics of telomere biology disorders
| Gene (protein product names) | Protein complex/function | Functional consequence of disease- associated mutation | TBD subtype | Mode of inheritance1 |
|---|---|---|---|---|
| DKC1 (DKC1, dyskerin) | Telomerase enzyme complex/telomerase assembly, TERC stability | Reduced TERC stability and telomerase activity | DC, HH, PF Female carriers may have subtle findings | XLR |
| TERC (hTR, human telomerase RNA component) | Telomerase enzyme complex/telomere elongation | Reduction of telomerase activity | DC, AA, PF, LD, MDS, AML, HH | AD |
| TERT (TERT, telomerase reverse transcriptase) | Telomerase enzyme complex/telomere elongation/telomerase recruitment | Reduction telomerase recruitment, processivity and/or activity | DC, AA, PF, LD, MDS, AML | AD |
| HH | AR | |||
| NOP 10 (NOP10, NOLA3, NOLA nuclear protein family A, member 3) | Telomerase enzyme complex/telomerase assembly, TERC stability | Reduced TERC stability and telomerase activity | DC | AR |
| NHP2 (NHP2, NOLA2, nucleolar protein family A, member 2) | Telomerase enzyme complex/telomerase assembly, TERC stability | Reduced TERC stability and telomerase activity | DC | AR |
| NAF1 (NAF1, nuclear assembly factor 1 ribonucleoprotein) | Telomerase enzyme complex/telomerase assembly, TERC stability | Reduced TERC stability and telomerase activity | PF, LD, MDS | AD |
| PARN (PARN, poly(A)-specific ribonuclease) | Associated with telomerase complex/TERC RNA maturation and stabilization | Reduced TERC stability and telomerase activity | PF | AD |
| DC, HH | AR | |||
| WRAP53 (TCAB1, telomere Cajal body associated protein 1) | Associated with telomerase complex/telomerase trafficking through Cajal bodies and recruitment | Impaired telomerase trafficking though Cajal body and recruitment to telomeres | DC, HH | AR |
| ACD (TPP1, telomere protection protein 1) | Shelterin enzyme complex: Telomerase recruitment, activity and processivity | Impaired telomerase recruitment | AA | AD |
| HH | AR | |||
| STN1 (STN1, CST complex subunit) | CST-complex/C-strand fill in, telomere replication | Impaired telomere replication | CP | AR |
| CTC1 (CTC1, conserved telomere maintenance component 1) | CST-complex/C-strand fill in, telomere replication | Impaired telomere replication, fragile telomeres | DC, CP | AR |
| RTEL1 (RTEL1, regulator of telomere elongation helicase 1) | Telomeric DNA replication/repair, t-loop stability and unwinding, prevention of telomere loss during cell division | Impaired telomere replication/stability | PF, AA, LD, DC | AD |
| DC, HH | AR | |||
| TINF2 (TIN2, TERF1 [TRF1]-interacting nuclear factor 2) | Shelterin enzyme complex/telomerase regulation, sister telomere cohesion, telomere protection from DDR, telomere recruitment | Multifactorial disruption of telomere maintenance | DC, HH, RS, PF | AD |
| POT1 (POT1, protection of telomeres 1) | Shelterin enzyme complex, interaction with CST complex, negative telomerase regulation, telomere protection from DDR | Defective telomerase regulation, dysfunctional telomere replication | CP | AR |
1
All mentioned gene alterations can occur de novo. Most frequently it is reported in TINF2 [84,85], and has also been reported for DKC1 [175]
Abbreviations: DC, dyskeratosis congenita; HH, Hoyeraal-Hreidarsson syndrome; RS, Revesz syndrome, CP, Coats plus; PF, pulmonary fibrosis; LD, liver disease; AA, aplastic anemia; XLR, X-linked recessive; AD, autosomal dominant; AR, autosomal recessive; DDR, DNA damage response