Germline variant of CTC1 gene in a patient with pulmonary fibrosis and myelodysplastic syndrome

Martina Doubkova; Zuzana Vrzalová; Marianna Štefániková; Libor Červinek; Kateřina Staňo Kozubik; Ivona Blaháková; Šárka Pospíšilová; Michael Doubek

doi:10.4081/mrm.2023.909

Germline variant of CTC1 gene in a patient with pulmonary fibrosis and myelodysplastic syndrome

Authors

Martina Doubkova Department of Pulmonary Diseases and Tuberculosis, University Hospital and Faculty of Medicine, Brno https://orcid.org/0000-0001-6536-3134
Zuzana Vrzalová Central European Institute of Technology, Masaryk University, Brno; Department of Internal Medicine - Hematology and Oncology, University Hospital and Faculty of Medicine, Brno
Marianna Štefániková Department of Pulmonary Diseases and Tuberculosis, University Hospital and Faculty of Medicine, Brno https://orcid.org/0009-0002-4164-8973
Libor Červinek Department of Internal Medicine - Hematology and Oncology, University Hospital and Faculty of Medicine, Brno
Kateřina Staňo Kozubik Central European Institute of Technology, Masaryk University, Brno; Department of Internal Medicine - Hematology and Oncology, University Hospital and Faculty of Medicine, Brno
Ivona Blaháková Central European Institute of Technology, Masaryk University, Brno; Department of Internal Medicine - Hematology and Oncology, University Hospital and Faculty of Medicine, Brno
Šárka Pospíšilová Central European Institute of Technology, Masaryk University, Brno; Department of Internal Medicine - Hematology and Oncology, and Department of Medical Genetics and Genomics, University Hospital and Faculty of Medicine, Brno
Michael Doubek Central European Institute of Technology, Masaryk University, Brno; Department of Internal Medicine - Hematology and Oncology, and Department of Medical Genetics and Genomics, University Hospital and Faculty of Medicine, Brno https://orcid.org/0000-0002-1269-6282

DOI: https://doi.org/10.4081/mrm.2023.909

Keywords:

CTC1 gene, interstitial pulmonary fibrosis, myelodysplastic syndrome

Abstract

Introduction: Telomeropathies are associated with a wide range of diseases and less common combinations of various pulmonary and extrapulmonary disorders.
Case presentation: In proband with high-risk myelodysplastic syndrome and interstitial pulmonary fibrosis, whole exome sequencing revealed a germline heterozygous variant of CTC1 gene (c.1360delG). This "frameshift" variant results in a premature stop codon and is classified as likely pathogenic/pathogenic. So far, this gene variant has been described in a heterozygous state in adult patients with hematological diseases such as idiopathic aplastic anemia or paroxysmal nocturnal hemoglobinuria, but also in interstitial pulmonary fibrosis. Described CTC1 gene variant affects telomere length and leads to telomeropathies.
Conclusions: In our case report, we describe a rare case of coincidence of pulmonary fibrosis and hematological malignancy caused by a germline gene mutation in CTC1. Lung diseases and hematologic malignancies associated with short telomeres do not respond well to standard treatment.

References

Broccoli D, Smogorzewska A, Chong L, de Lange T. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat Genet 1997;17:231-5.

de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 2005;19:2100-10.

Wellinger RJ. The CST complex and telomere maintenance: the exception becomes the rule. Mol Cell 2009;36:168-9.

Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia 2022;36:1703-19.

Shen W, Kerr CM, Przychozen B, Mahfouz RZ, LaFramboise T, Nagata Y, et al. Impact of germline CTC1 alterations on telomere length in acquired bone marrow failure. Br J Haematol 2019;185:935-9.

Rice C, Skordalakes E. Structure and function of the telomeric CST complex. Comput Struct Biotechnol J 2016;14:161-7.

Sargolzaeiaval F, Zhang J, Schleit J, Lessel D, Kubisch C, Precioso DR, et al. CTC1 mutations in a Brazilian family with progeroid features and recurrent bone fractures. Mol Genet Genomic Med 2018;6:1148-56.

Anderson BH, Kasher PR, Mayer J, Szynkiewicz M, Jenkinson EM, Bhaskar SS, et al. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat Genet 2012;44:338-42.

Huang C, Jia P, Chastain M, Shiva O, Chai W. The human CTC1/STN1/TEN1 complex regulates telomere maintenance in ALT cancer cells. Exp Cell Res 2017;355:95-104.

Chen LY, Redon S, Lingner J. The human CST complex is a terminator of telomerase activity. Nature 2012;488:540-4.

Townsley DM, Dumitriu B, Young NS. Bone marrow failure and the telomeropathies. Blood 2014;124:2775-83.

Armanios M. Telomerase and idiopathic pulmonary fibrosis. Mutat Res 2012;730:52-8.

Arias-Salgado EG, Galvez E, Planas-Cerezales L, Pintado-Berninches L, Vallespin E, Martinez P, et al. Genetic analyses of aplastic anemia and idiopathic pulmonary fibrosis patients with short telomeres, possible implication of DNA-repair genes. Orphanet J Rare Dis 2019;14:82.

Barbaro PM, Ziegler DS, Reddel RR. The wide-ranging clinical implications of the short telomere syndromes. Intern Med J 2016;46:393-403.

Rizvi S, Raza ST, Mahdi F. Telomere length variations in aging and age-related diseases. Curr Aging Sci 2014;7:161-7.

Keller RB, Gagne KE, Usmani GN, Asdourian GK, Williams DA, Hofmann I, et al. CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer 2012;59:311-4.

Lin H, Gong L, Zhan S, Wang Y, Liu A. Novel biallelic missense mutations in CTC1 gene identified in a Chinese family with Coats plus syndrome. J Neurol Sci 2017;382:142-5.

Walne AJ, Bhagat T, Kirwan M, Gitiaux C, Desguerre I, Leonard N, et al. Mutations in the telomere capping complex in bone marrow failure and related syndromes. Haematologica 2013;98:334-8.

Polvi A, Linnankivi T, Kivelä T, Herva R, Keating JP, Mäkitie O, et al. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am J Hum Genet 2012;90:540-9.

Vieri M, Kirschner M, Tometten M, Abels A, Rolles B, Isfort S, et al. Comparable effects of the androgen derivatives danazol, oxymetholone and nandrolone on telomerase activity in human primary hematopoietic cells from patients with dyskeratosis congenita. Int J Mol Sci 2020;21:7196.

Chambers DC, Lutzky VP, Apte SH, Godbolt D, Feenstra J, Mackintosh J. Successful treatment of telomeropathy-related interstitial lung disease with immunosuppression and danazol. Respirol Case Rep 2020;8:e00607.