Triallelic and epigenetic-like inheritance in human disorders of telomerase

Collopy, Laura C.; Walne, Amanda J.; Cardoso, Shirleny; Fuente, Josu de la; Mohamed, Mahfuzah; Toriello, Helga V.; Tamary, Hannah; Ling, Adam J. Y. V.; Lloyd, Timothy; Kassam, Rebecca; Tummala, Hemanth; Vulliamy, Thomas J.; Dokal, Inderjeet

doi:10.1182/blood-2015-03-633388

Cited by 55 publications

(35 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Constitutional BMF, especially in adults, is likely underreported, because of incomplete penetrance, reduced expressivity, and disease anticipation, as well as a lack of awareness by clinicians that it may present without mucocutaneous features and instead with pulmonary fibrosis or cirrhosis. 26 The importance of the diagnosis of an inherited BMF disorder is highlighted in our study. First, there are implications for donor selection and choice of transplantconditioning regimen in hematopoietic stem cell transplantation (HSCT).…”

Section: Discussionmentioning

confidence: 82%

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

et al. 2018

View full text Add to dashboard Cite

Key Points• RTEL1 variants associate with AA, idiopathic cytopenias, and hypocellular myelodysplastic syndromes.• Detailed clinical/family history, functional assays, and in silico tools are critical for interpreting the pathogenicity of RTEL1 variants.Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n 5 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n 5 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 39 telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants.Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

show abstract

Section: Discussionmentioning

confidence: 82%

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In the future, it would be interesting to study the interaction of these IFD variants with other telomerase-associated proteins, including the negative regulators hPif (61)(62)(63), the regulator of telomerase activity and recruitment PinX1 (64,65), TIN2 (66), and HOT1 (homeobox telomere-binding protein 1) (67). Furthermore, clinical data from two newly identified mutations in the IFD (M773T and V777L) strongly suggest that these variants might be disease-causing TERT variants (68). Understanding the biochemical and molecular defects of these and other mutant telomerase enzymes would be of primary importance for the design of therapeutic treatments.…”

Section: Discussionmentioning

confidence: 99%

Multiple Mechanisms Contribute to the Cell Growth Defects Imparted by Human Telomerase Insertion in Fingers Domain Mutations Associated with Premature Aging Diseases

Chu

MacNeil

Autexier

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Normal human stem cells rely on low levels of active telomerase to sustain their high replicative requirements. Deficiency in telomere maintenance mechanisms leads to the development of premature aging diseases, such as dyskeratosis congenita and aplastic anemia. Mutations in the unique "insertion in fingers domain" (IFD) in the human telomerase reverse transcriptase catalytic subunit (hTERT) have previously been identified and shown to be associated with dyskeratosis congenita and aplastic anemia. However, little is known about the molecular mechanisms impacted by these IFD mutations. We performed comparative functional analyses of disease-associated IFD variants at the molecular and cellular levels. We report that hTERT-P721R-and hTERT-R811C-expressing cells exhibited growth defects likely due to impaired TPP1-mediated recruitment of these variant enzymes to telomeres. We showed that activity and processivity of hTERT-T726M failed to be stimulated by TPP1-POT1 overexpression and that dGTP usage by this variant was less efficient compared with the wild-type enzyme. hTERT-P785L-expressing cells did not show growth defects, and this variant likely confers cell survival through increased DNA synthesis and robust activity stimulation by TPP1-POT1. Altogether, our data suggest that multiple mechanisms contribute to cell growth defects conferred by the IFD variants.

show abstract

“…Phenocopy is defined in this review in a familial context of pulmonary fibrosis as an affected relative with a different genotype from the proband. This epigenetic-like inheritance in human disorders of telomerase explains the occurrence of phenocopies (an affected patient without the familial mutation) [17,43] and the phenomenon of genetic anticipation, defined by an earlier onset of the disease with each generation (figure 2) [17,43,44], and this complicates genetic counselling. Because telomere shortening varies depending on the involved gene and its impact on telomere length, genetic anticipation may be more pronounced for carriers of TERC than PARN mutations [9].…”

Section: Asymptomatic Involvementmentioning

confidence: 99%

Management of suspected monogenic lung fibrosis in a specialised centre

et al. 2017

View full text Add to dashboard Cite

At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis.Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed.The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team.

show abstract

Triallelic and epigenetic-like inheritance in human disorders of telomerase

Cited by 55 publications

References 49 publications

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

Multiple Mechanisms Contribute to the Cell Growth Defects Imparted by Human Telomerase Insertion in Fingers Domain Mutations Associated with Premature Aging Diseases

Management of suspected monogenic lung fibrosis in a specialised centre

Contact Info

Product

Resources

About