Article
Hematology
Martin Kirschner, Margherita Vieri, Kim Kricheldorf, Monica S. Ventura Ferreira, Marcin W. Wlodarski, Michaela Schwarz, Stefan Balabanov, Benjamin Rolles, Susanne Isfort, Steffen Koschmieder, Britta Hoechsmann, Jens Panse, Tim H. Bruemmendorf, Fabian Beier
Summary: AD treatment for DKC patients resulted in hematological response, significant increase in telomere length of lymphocytes and granulocytes, and no detection of MDS-related mutations. Pending longer follow-up, AD treatment appears to be an efficient and safe therapy for DKC patients.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Hematology
Hannah A. Raj, Tsung-Po Lai, Marena R. Niewisch, Neelam Giri, Youjin Wang, Stephen R. Spellman, Abraham Aviv, Shahinaz M. Gadalla, Sharon A. Savage
Summary: Individuals with telomere biology disorders (TBDs) have significantly shortened telomeres in blood cells, which is associated with increased risk of bone marrow failure and reduced survival. The mean telomere length is estimated to be 5 kilobases, but it is the shortest telomeres that indicate cellular senescence. By using the Telomere Shortest Length Assay (TeSLA), it was found that TBD patients have much shorter mean telomere length and an increased number of telomeres less than 3 kilobases. In addition, TBD patients with severe bone marrow failure and multiple organ manifestations have even shorter telomeres.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Hematology
Christopher R. Reilly, Mikko Myllymaki, Robert Redd, Shilpa Padmanaban, Druha Karunakaran, Valerie Tesmer, Frederick D. Tsai, Christopher J. Gibson, Huma Q. Rana, Liang Zhong, Wael Saber, Stephen R. Spellman, Zhen-Huan Hu, Esther H. Orr, Maxine M. Chen, Immaculata De Vivo, Daniel J. DeAngelo, Corey Cutler, Joseph H. Antin, Donna Neuberg, Judy E. Garber, Jayakrishnan Nandakumar, Suneet Agarwal, R. Coleman Lindsley
Summary: Research indicates that rare TERT variants are associated with an increased risk of developing MDS and nonrelapse mortality, with 90% of the variants showing impairment in telomere elongation function. Routine screening for TERT rare variants in MDS patients may enhance transplant outcomes.
Article
Multidisciplinary Sciences
Jesus Garcia-Castillo, Francisca Alcaraz-Perez, Elena Martinez-Balsalobre, Diana Garcia-Moreno, Marlies P. Rossmann, Miriam Fernandez-Lajarin, Manuel Bernabe-Garcia, Ana B. Perez-Oliva, Virginia C. Rodriguez-Cortez, Clara Bueno, Isaac Adatto, Suneet Agarwal, Pablo Menendez, Leonard Zon, Victoriano Mulero, Maria L. Cayuela
Summary: Dyskeratosis congenita (DC) is a rare genetic syndrome caused by mutations in telomerase or telomeric proteins. Research shows that zebrafish terc plays a crucial role in regulating the expression of master myeloid genes, while mutations found in DC patients affect this process.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Sherilyn Grill, Jayakrishnan Nandakumar
Summary: Genetic mutations affecting telomerase function or telomere maintenance can lead to a range of diseases collectively referred to as telomeropathies, including dyskeratosis congenita. These diseases are characterized by severely shortened telomeres, often resulting in hematopoietic stem cell failure. Recent research has focused on understanding the molecular basis of these diseases, with mutations impacting telomerase activity, recruitment of telomerase to the telomere, and telomere replication defects.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Immunology
Benjamin Rolles, Andres Caballero-Oteyza, Michele Proietti, Sigune Goldacker, Klaus Warnatz, Nadezhda Camacho-Ordonez, Seraina Prader, Jana Pachlopnik Schmid, Margherita Vieri, Susanne Isfort, Robert Meyer, Martin Kirschner, Tim H. Bruemmendorf, Fabian Beier, Bodo Grimbacher
Summary: Telomere biology disorders (TBD) are genetic diseases caused by pathogenic variants in genes related to telomere maintenance. TBD can manifest in adulthood and have variable symptoms, making diagnosis complicated. Common variable immunodeficiency (CVID) is an antibody deficiency syndrome caused by dysfunctional B lymphocytes. In our study, we found that approximately 22% of CVID patients carried rare candidate variants in telomere-associated genes. We recommend including all TBD-associated genes in the genetic screening of patients with antibody deficiencies.
CLINICAL IMMUNOLOGY
(2023)
Review
Genetics & Heredity
Patrick Revy, Caroline Kannengiesser, Alison A. Bertuch
Summary: This article reviews the confirmed and potential genes causing telomere diseases and describes their main functions in telomere biology. The authors also discuss the genetic features underlying the complexity of these diseases.
NATURE REVIEWS GENETICS
(2023)
Review
Biochemistry & Molecular Biology
Luis F. Z. Batista, Inderjeet Dokal, Roy Parker
Summary: Telomere biology disorders are rare diseases caused by mutations that impair telomere maintenance, leading to clinical manifestations such as bone marrow failure, pulmonary fibrosis, and liver cirrhosis. There are currently no curative therapies for TBD patients, but research on telomerase RNA component has identified potential therapeutic approaches for further investigation in clinical trials.
TRENDS IN MOLECULAR MEDICINE
(2022)
Article
Medicine, General & Internal
Mone't B. Thompson, Daniel Muldoon, Kelvin C. de Andrade, Neelam Giri, Blanche P. Alter, Sharon A. Savage, Robert D. Shamburek, Payal P. Khincha
Summary: The study found that oral androgen therapy in DC patients altered lipid and lipoprotein levels, potentially increasing the risk of atherogenic cardiovascular disease. Individuals on androgens for DC-related BMF should undergo cardiovascular disease monitoring.
Article
Biochemistry & Molecular Biology
Jian Qin, Alexandre Garus, Chantal Autexier
Summary: This study reveals that mutations in the C-terminal extension (CTE) of dyskerin impair its interaction with hTR, leading to X-linked dyskeratosis congenita (X-DC) and related telomere syndromes. These mutations result in reduced binding to SHQ1 and defective binding to hTR. Furthermore, deletion of the CTE further reduces binding to hTR and disrupts the localization and interaction of dyskerin with other molecules.
HUMAN MOLECULAR GENETICS
(2023)
Article
Endocrinology & Metabolism
Z. Belaya, O. Golounina, A. Nikitin, N. Tarbaeva, E. Pigarova, E. Mamedova, M. Vorontsova, I. Shafieva, I. Demina, W. Van Hul
Summary: A young male patient with clinical signs of dyskeratosis congenita presented with multiple bilateral low-traumatic hip fractures. Whole exome sequencing revealed a previously unreported mutation in the PARN gene. Treatment with zoledronic acid was effective at preventing further fractures.
OSTEOPOROSIS INTERNATIONAL
(2021)
Article
Cell & Tissue Engineering
Carlos Carrascoso-Rubio, Hidde A. Zittersteijn, Laura Pintado-Berninches, Beatriz Fernandez-Varas, M. Luz Lozano, Cristina Manguan-Garcia, Leandro Sastre, Juan A. Bueren, Rosario Perona, Guillermo Guenechea
Summary: Dyskeratosis congenita (DC) is a rare genetic disorder causing bone marrow failure. Current curative treatment involves allogeneic hematopoietic stem cell transplantation. This study successfully generated DC-like human hematopoietic stem cells to investigate innovative therapies and understand the molecular basis of the disease.
STEM CELL RESEARCH & THERAPY
(2021)
Review
Genetics & Heredity
Michelle L. W. Kam, Trang T. T. Nguyen, Joanne Y. Y. Ngeow
Summary: Telomere biology disorders are a group of diseases caused by germline mutations affecting genes responsible for telomere maintenance. These disorders present with a range of symptoms such as bone marrow failure, pulmonary fibrosis, and are often difficult to diagnose due to variable clinical manifestations. There is currently no standardized diagnostic criteria, limited treatment options, and poor prognosis associated with organ transplantation.
NPJ GENOMIC MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Bartosz Malinski, Jacopo Vertemara, Elena Faustini, Claes Ladenvall, Anna Norberg, Yuming Zhang, Eleonore von Castelmur, Panagiotis Baliakas, Renata Tisi, Jorg Cammenga, Francisca Lottersberger
Summary: Telomere biology disorders (TBDs) are characterized by short telomeres, premature aging, bone marrow failure and cancer predisposition. In this study, two novel NHP2 variants (NHP2-A39T and NHP2-T44M) were identified in a patient with premature aging, bone marrow failure/myelodysplastic syndrome and gastric cancer. These variants reduce the levels of hTR and telomerase activity, and fail to be incorporated in the H/ACA RNA binding complex, leading to their degradation and disease manifestation.
HUMAN MOLECULAR GENETICS
(2023)
Review
Hematology
Jiayi Geng, Menglin Zhao, Qiuyu Li
Summary: This article reports a case of a 27-year-old woman who had pancytopenia for 4 months and dyspnea with coughing for 7 days. She was diagnosed with non-Hodgkin's lymphoma 5 months ago. During immunochemotherapy, she experienced recurrent fever, oral ulcer, pancytopenia, dyspnea and other symptoms. On admission, her respiratory symptoms worsened, she had recurrent infections and acute heart failure. Laboratory examination confirmed pancytopenia, and chest CT revealed interstitial lung disease (ILD). Genetic analysis confirmed the presence of DC and a TINF2 gene mutation. With continuous supportive and anti-infection treatment, her condition finally stabilized. She was discharged after nearly 2 months.