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Dyskeratosis Congenita

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https://www.readbyqxmd.com/read/29770205/beginning-at-the-ends-telomeres-and-human-disease
#1
REVIEW
Sharon A Savage
Studies of rare and common illnesses have led to remarkable progress in the understanding of the role of telomeres (nucleoprotein complexes at chromosome ends essential for chromosomal integrity) in human disease. Telomere biology disorders encompass a growing spectrum of conditions caused by rare pathogenic germline variants in genes encoding essential aspects of telomere function. Dyskeratosis congenita, a disorder at the severe end of this spectrum, typically presents in childhood with the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia, accompanied by a very high risk of bone marrow failure, cancer, pulmonary fibrosis, and other medical problems...
2018: F1000Research
https://www.readbyqxmd.com/read/29749397/recurrent-somatic-mutations-are-rare-in-patients-with-cryptic-dyskeratosis-congenita
#2
Martin Kirschner, Angela Maurer, Marcin W Wlodarski, Monica S Ventura Ferreira, Anne-Sophie Bouillon, Insa Halfmeyer, Wolfgang Blau, Michael Kreuter, Martin Rosewich, Selim Corbacioglu, Joachim Beck, Michaela Schwarz, Jörg Bittenbring, Markus P Radsak, Christian Matthias Wilk, Steffen Koschmieder, Matthias Begemann, Ingo Kurth, Mirle Schemionek, Tim H Brümmendorf, Fabian Beier
Dyskeratosis congenita (DKC) is a paradigmatic telomere disorder characterized by substantial and premature telomere shortening, bone marrow failure, and a dramatically increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). DKC can occur as a late-onset, so-called cryptic form, with first manifestation in adults. Somatic MDS-related mutations are found in up to 35% of patients with acquired aplastic anemia (AA), especially in patients with short telomeres. The aim of our study was to investigate whether cryptic DKC is associated with an increased incidence of MDS-related somatic mutations, thereby linking the accelerated telomere shortening with the increased risk of MDS/AML...
April 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29742735/a-case-report-of-heterozygous-tinf2-gene-mutation-associated-with-pulmonary-fibrosis-in-a-patient-with-dyskeratosis-congenita
#3
Hongchun Du, Yubiao Guo, Di Ma, Kejing Tang, Decheng Cai, Yifeng Luo, Canmao Xie
RATIONALE: Dyskeratosis congenita (DC) is a rare inherited disease characterized by the classical mucocutaneous triad. Pulmonary fibrosis, bone marrow failure, and solid tumors are the main causes of mortality in DC. Pathogenic variants in TERT, TERC, and DKC1 have been identified in individuals with familial pulmonary fibrosis. Mutations in TINF2 gene have been reported to be associated with bone marrow failure in most cases. However, the relationship between TINF2 mutation and pulmonary fibrosis is not yet clear...
May 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29734785/the-guardian-of-the-genome-revisited-p53-downregulates-genes-required-for-telomere-maintenance-dna-repair-and-centromere-structure
#4
REVIEW
Eléonore Toufektchan, Franck Toledo
The p53 protein has been extensively studied for its capacity to prevent proliferation of cells with a damaged genome. Surprisingly, however, our recent analysis of mice expressing a hyperactive mutant p53 that lacks the C-terminal domain revealed that increased p53 activity may alter genome maintenance. We showed that p53 downregulates genes essential for telomere metabolism, DNA repair, and centromere structure and that a sustained p53 activity leads to phenotypic traits associated with dyskeratosis congenita and Fanconi anemia...
May 6, 2018: Cancers
https://www.readbyqxmd.com/read/29722029/a-regulatory-loop-connecting-wnt-signaling-and-telomere-capping-possible-therapeutic-implications-for-dyskeratosis-congenita
#5
REVIEW
Rafael Jesus Fernandez, F Brad Johnson
The consequences of telomere dysfunction are most apparent in rare inherited syndromes caused by genetic deficiencies in factors that normally maintain telomeres. The principal disease is known as dyskeratosis congenita (DC), but other syndromes with similar underlying genetic defects share some clinical aspects with this disease. Currently, there are no curative therapies for these diseases of telomere dysfunction. Here, we review recent findings demonstrating that dysfunctional (i.e., uncapped) telomeres can downregulate the WNT pathway, and that restoration of WNT signaling helps to recap telomeres by increasing expression of shelterins, proteins that naturally bind and protect telomeres...
April 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29703930/whole-exome-sequencing-reveals-rare-variants-linked-to-congenital-pouch-colon
#6
Praveen Mathur, Krishna Mohan Medicherla, Spandan Chaudhary, Mruduka Patel, Prashanth Bagali, Prashanth Suravajhala
We demonstrate the application of whole exome sequencing to discover the rare variants for congenital pouch colon, acronymed CPC. For 18 affected individuals in a total of 64 samples, we sequenced coding regions to a mean coverage of 100×. A sufficient depth of ca. 94% of targeted exomes was achieved. Filtering against the public SNP/variant repositories, we identified a host of candidate genes, EPB41L4A and CTC1 associated with colon, neural/brain muscles and Dyskeratosis Congenita maladies. Furthermore, the stop gain mutations in the form of JAG1,OR5AR1,SLC22A24,PEX16,TSPAN32,TAF1B,MAP2K3 and SLC25A19 appears to be localized to Chromosomes 2, 11, 17 and 20 in addition to the three stop lost mutants across three genes, viz...
April 27, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29700810/refining-the-phenotype-associated-with-biallelic-dnajc21-mutations
#7
G D'Amours, F Lopes, J Gauthier, V Saillour, C Nassif, R Wynn, N Alos, T Leblanc, Y Capri, S Nizard, E Lemyre, J L Michaud, V-A Pelletier, Y D Pastore, J-F Soucy
Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of five unreported affected children and all individuals reported in the literature...
April 26, 2018: Clinical Genetics
https://www.readbyqxmd.com/read/29696773/complex-phenotype-of-dyskeratosis-congenita-and-mood-dysregulation-with-novel-homozygous-rtel1-and-tph1-variants
#8
Rachel A Ungar, Neelam Giri, Maryland Pao, Payal P Khincha, Weiyin Zhou, Blanche P Alter, Sharon A Savage
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by germline mutations in telomere biology genes. Patients have extremely short telomeres for their age and a complex phenotype including oral leukoplakia, abnormal skin pigmentation, and dysplastic nails in addition to bone marrow failure, pulmonary fibrosis, stenosis of the esophagus, lacrimal ducts and urethra, developmental anomalies, and high risk of cancer. We evaluated a patient with features of DC, mood dysregulation, diabetes, and lack of pubertal development...
April 25, 2018: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29581185/the-c-terminal-extension-unique-to-the-long-isoform-of-the-shelterin-component-tin2-enhances-its-interaction-with-trf2-in-a-phosphorylation-and-dyskeratosis-congenita-cluster-dependent-fashion
#9
Nya D Nelson, Lois M Dodson, Laura Escudero, Ann T Sukumar, Christopher L Williams, Ivana Mihalek, Alessandro Baldan, Duncan M Baird, Alison A Bertuch
TIN2 is central to the shelterin complex, linking the telomeric proteins TRF1 and TRF2 with TPP1/POT1. Mutations in TINF2 , which encodes TIN2, that are found in dyskeratosis congenita (DC) result in very short telomeres and cluster in a region shared by the two TIN2 isoforms, TIN2S (short) and TIN2L (long). Here we show that TIN2L, but not TIN2S, is phosphorylated. TRF2 interacts more with TIN2L than TIN2S, and both the DC-cluster and phosphorylation promote this enhanced interaction. The binding of TIN2L, but not TIN2S, is affected by TRF2-F120, which is also required for TRF2's interaction with end processing factors such as Apollo...
March 26, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29550946/the-role-of-telomere-binding-molecules-for-normal-and-abnormal-hematopoiesis
#10
REVIEW
Kentaro Hosokawa, Fumio Arai
In order to maintain the homeostasis of the hematopoietic system, hematopoietic stem cells (HSCs) need to be maintained while slowly dividing over their lifetime. However, repeated cell divisions lead to the gradual accumulation of DNA damage and ultimately impair HSC function. Since telomeres are particularly fragile when subjected to replication stress, cells have several defense machinery to protect telomeres. Moreover, HSCs must protect their genome against possible DNA damage, while maintaining telomere length...
March 17, 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29522136/human-rtel1-stabilizes-long-g-overhangs-allowing-telomerase-dependent-over-extension
#11
Rosa M Porreca, Galina Glousker, Aya Awad, Maria I Matilla Fernandez, Anne Gibaud, Christian Naucke, Scott B Cohen, Tracy M Bryan, Yehuda Tzfati, Irena Draskovic, Arturo Londoño-Vallejo
Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase...
March 7, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29514627/a-unique-homozygous-wrap53-arg298trp-mutation-underlies-dyskeratosis-congenita-in-a-chinese-han-family
#12
Yingqi Shao, Sizhou Feng, Jinbo Huang, Jiali Huo, Yahong You, Yizhou Zheng
BACKGROUND: Dyskeratosis congenita (DC) is an inherited telomeropathy characterized by mucocutaneous dysplasia, bone marrow failure, cancer predisposition, and other somatic abnormalities. Cells from patients with DC exhibit short telomere. The genetic basis of the majority of DC cases remains unknown. METHODS: A 2 generational Chinese Han family with DC was studied using targeted capture and next-generation sequencing to identify the underlying DC-related mutations...
March 7, 2018: BMC Medical Genetics
https://www.readbyqxmd.com/read/29422759/cytomegalovirus-retinitis-as-a-presenting-feature-of-multisystem-disorder-dyskeratosis-congenita
#13
Swapnil Parchand, Adarsh Barwad
Cytomegalovirus (CMV) retinitis is an opportunistic infection commonly seen in disorders that affect the immune system of the body such as acquired immunodeficiency syndrome and hematological malignancies such as leukemia/lymphoma or organ transplantation. The occurrence of CMV retinitis in the absence of such condition should be thoroughly investigated, as it is a strong indicator of poor immune competence. We here report an interesting case of CMV retinitis as a presenting feature of rare multisystem disorde r "Dyskeratosis congenita...
October 2017: Middle East African Journal of Ophthalmology
https://www.readbyqxmd.com/read/29344583/heterozygous-rtel1-variants-in-bone-marrow-failure-and-myeloid-neoplasms
#14
Judith C W Marsh, Fernanda Gutierrez-Rodrigues, James Cooper, Jie Jiang, Shreyans Gandhi, Sachiko Kajigaya, Xingmin Feng, Maria Del Pilar F Ibanez, Flávia S Donaires, João P Lopes da Silva, Zejuan Li, Soma Das, Maria Ibanez, Alexander E Smith, Nicholas Lea, Steven Best, Robin Ireland, Austin G Kulasekararaj, Donal P McLornan, Anthony Pagliuca, Isabelle Callebaut, Neal S Young, Rodrigo T Calado, Danielle M Townsley, Ghulam J Mufti
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 = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59)...
January 9, 2018: Blood Advances
https://www.readbyqxmd.com/read/29222242/treatment-of-inherited-bone-marrow-failure-syndromes-beyond-transplantation
#15
REVIEW
Rodrigo T Calado, Diego V Clé
Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29222241/inherited-bone-marrow-failure-syndromes-considerations-pre-and-posttransplant
#16
REVIEW
Blanche P Alter
Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29178645/inherited-shq1-mutations-impair-interaction-with-nap57-dyskerin-a-major-target-in-dyskeratosis-congenita
#17
Jonathan Bizarro, U Thomas Meier
BACKGROUND: The inherited bone marrow failure syndrome dyskeratosis congenita (DC) is most frequently caused by mutations in DKC1 (MIM# 300126), the gene encoding NAP57 (aka dyskerin). The typically missense mutations modulate the interaction of NAP57 with its chaperone SHQ1, but no DC mutations have been identified in SHQ1 (MIM# 613663). Here, we report on two compound heterozygous mutations in SHQ1 in a patient with a severe neurological disorder including cerebellar degeneration. METHODS: The SHQ1 mutations were identified by patient exome sequencing...
November 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/29167174/inherited-bone-marrow-failure-syndromes-considerations-pre-and-posttransplant
#18
REVIEW
Blanche P Alter
Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome...
November 23, 2017: Blood
https://www.readbyqxmd.com/read/29161159/unilateral-coats-like-disease-and-an-intragenic-deletion-in-the-terc-gene-a-case-report
#19
G Peene, E Smets, E Legius, C Cassiman
We report a case of a 25-year-old woman with unilateral Coats'-like disease. Her brother was previously diagnosed with an autosomal dominant form of dyskeratosis congenita. Genetic testing was performed by screening the TERC gene for mutations and identified heterozygosity for the n.68_124del mutation. Our case demonstrates that the exudative retinopathy seen in Coats'-like disease can be caused by mutations in a telomere-capping gene TERC as a part of the dyskeratosis congenita spectrum without other systemic involvement...
April 2018: Ophthalmic Genetics
https://www.readbyqxmd.com/read/29081935/clinical-heterogeneity-in-a-family-with-dkc1-mutation-dyskeratosis-congenita-and-hoyeraal-hreidarsson-syndrome-in-first-cousins
#20
Cristina Olivieri, Anna Mondino, Matteo Chinello, Alessandra Risso, Enrico Finale, Marina Lanciotti, Andrea Guala
Dyskeratosis congenita (DC) is an inherited bone marrow failure disorder characterized by mucocutaneous features (skin pigmentation, nail dystrophy and oral leukoplakia), pulmonary fibrosis, hematologic and solid malignancies. Its severe form, recognized as Hoyeraal-Hreidarsson syndrome (HHS), also includes cerebellar hypoplasia, microcephaly, developmental delay and prenatal growth retardation. In literature phenotypic variability among DC patients sharing the same mutation is wellknown. To our knowledge this report describes for the first time a family of DC patients, characterized by a member with features of classic DC and another one with some features of HHS, both with the same mutation in DKC1 ...
October 6, 2017: Pediatric Reports
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