A child with severe form of dyskeratosis congenita and TINF2 mutation of shelterin complex

2010 ◽  
Vol 55 (6) ◽  
pp. 1185-1186 ◽  
Author(s):  
Nazan Sarper ◽  
Emine Zengin ◽  
Suar Çakı Kılıç
Keyword(s):  
Dyskeratosis Congenita ◽  
Severe Form ◽  
Shelterin Complex

scholarly journals 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

2018 ◽  
Vol 38 (12) ◽  
Author(s):  
Nya D. Nelson ◽  
Lois M. Dodson ◽  
Laura Escudero ◽  
Ann T. Sukumar ◽  
Christopher L. Williams ◽  
...  
Keyword(s):  
Cell Lines ◽  
Dyskeratosis Congenita ◽  
Telomere Elongation ◽  
Shelterin Complex ◽  
Short Palindromic Repeat ◽  
Processing Factors

ABSTRACT 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. Conversely, TRF1 interacts more with TIN2S than with TIN2L. A DC-associated mutation further reduces TIN2L-TRF1, but not TIN2S-TRF1, interaction. Cells overexpressing TIN2L or phosphomimetic TIN2L are permissive to telomere elongation, whereas cells overexpressing TIN2S or phosphodead TIN2L are not. Telomere lengths are unchanged in cell lines in which TIN2L expression has been eliminated by clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated mutation. These results indicate that TIN2 isoforms are biochemically and functionally distinguishable and that shelterin composition could be fundamentally altered in patients with TINF2 mutations.

scholarly journals Clinical heterogeneity in a family with DKC1 mutation, dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome in first cousins

2017 ◽  
Vol 9 (3) ◽  
Author(s):  
Cristina Olivieri ◽  
Anna Mondino ◽  
Matteo Chinello ◽  
Alessandra Risso ◽  
Enrico Finale ◽  
...  
Keyword(s):  
Bone Marrow Failure ◽  
Phenotypic Variability ◽  
Skin Pigmentation ◽  
Dyskeratosis Congenita ◽  
Severe Form ◽  
Nail Dystrophy ◽  
Prenatal Growth ◽  
Solid Malignancies ◽  
Hematological Manifestations ◽  
First Time

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 <em>DKC1</em>. Our family confirms again that one mutation can be associated with different phenotypes and different hematological manifestations. It’s possible to speculate that there are likely to be patients who do not clinically fit neatly into either classical DC or HHS, but whose clinical features are due to mutations in <em>DKC1</em> or in genes responsible for autosomal DC/HHS.

NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Høyeraal–Hreidarsson syndrome

2020 ◽  
Vol 29 (6) ◽  
pp. 907-922 ◽  
Author(s):  
Maname Benyelles ◽  
Marie-Françoise O’Donohue ◽  
Laëtitia Kermasson ◽  
Elodie Lainey ◽  
Raphael Borie ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Telomere Length ◽  
Wide Spectrum ◽  
Bone Marrow Failure ◽  
Selective Advantage ◽  
Dyskeratosis Congenita ◽  
Severe Form ◽  
Premature Aging ◽  
Missense Mutations ◽  
First Case

Abstract Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR and several cofactors, including the H/ACA box ribonucleoproteins Dyskerin, NOP10, GAR1, NAF1 and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal–Hreidarsson syndrome, the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Finally, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.

scholarly journals PARN Modulates Y RNA Stability and Its 3′-End Formation

2017 ◽  
Vol 37 (20) ◽  
Author(s):  
Siddharth Shukla ◽  
Roy Parker
Keyword(s):  
Mammalian Cells ◽  
Rna Stability ◽  
Rna Degradation ◽  
Dyskeratosis Congenita ◽  
Severe Form ◽  
Loss Of Function ◽  
Severe Phenotype ◽  
Complex Process ◽  
The Stability ◽  
Human Telomerase

ABSTRACT Loss-of-function mutations in 3′-to-5′ exoribonucleases have been implicated in hereditary human diseases. For example, PARN mutations cause a severe form of dyskeratosis congenita (DC), wherein PARN deficiency leads to human telomerase RNA instability. Since the DC phenotype in PARN patients is even more severe than that of loss-of-function alleles in telomerase components, we hypothesized that PARN would also be required for the stability of other RNAs. Here, we show that PARN depletion reduces the levels of abundant human Y RNAs, which might contribute to the severe phenotype of DC observed in patients. Depletion of PAPD5 or the cytoplasmic exonuclease DIS3L rescues the effect of PARN depletion on Y RNA levels, suggesting that PARN stabilizes Y RNAs by removing oligoadenylated tails added by PAPD5, which would otherwise recruit DIS3L for Y RNA degradation. Through deep sequencing of 3′ ends, we provide evidence that PARN can also deadenylate the U6 and RMRP RNAs without affecting their levels. Moreover, we observed widespread posttranscriptional oligoadenylation, uridylation, and guanylation of U6 and Y RNA 3′ ends, suggesting that in mammalian cells, the formation of a 3′ end for noncoding RNAs can be a complex process governed by the activities of various 3′-end polymerases and exonucleases.

scholarly journals A Case Report on a Rare Inherited Bone Marrow Failure Syndrome: Dyskeratosis Congenita.

2020 ◽  
Vol 44 (2) ◽  
pp. 122-125
Author(s):  
Md Anwarul Karim ◽  
Chowdhury Yakub Jamal ◽  
Md Imrul Kaes ◽  
Khondaker Mobasher Ahmed
Keyword(s):  
Bone Marrow ◽  
Case Report ◽  
Ectodermal Dysplasia ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Severe Form ◽  
Causal Mechanism ◽  
Rare Type ◽  
Bone Marrow Failure Syndrome ◽  
Bone Marrow Disease

Dyskeratosis congenita is a rare type of inherited bone marrow failure syndromes (IBMFs) characterized by ectodermal dysplasia, bone marrow failure and cancer predisposition. Accelerated telomere shortening is supposed to be the causal mechanism of this disease. Features of ectodermal dysplasia appears early and may give clues of suspicion of forthcoming bone marrow disease. It has variable presentation and severe form of disease presents earlier. This a case report on a 2 year 2-month old boy who presented with features of bone marrow failure and had abnormality of skin, nail and oral mucosa. Bangladesh J Child Health 2020; VOL 44 (2) :122-125

Hämophilie-Zentrum Bonn 1980 – 2009

2011 ◽  
Vol 31 (S 01) ◽  
pp. S4-S10 ◽  
Author(s):  
I. Besmens ◽  
H.-H. Brackmann ◽  
J. Oldenburg
Keyword(s):  
Young Patients ◽  
Severe Form ◽  
Coagulation Disorder ◽  
Care Providers ◽  
Long Distance ◽  
Patient Age ◽  
Patient Âgé ◽  
Number Of Patients ◽  
Clotting Disorder ◽  
Regional Character

SummaryThe Bonn Haemophilia Care Center provides patient care on a superregional level. The centre’s large service area is, in part, due to the introduction of haemophilia home treatment and related to this the individualized prophylaxis in children and adults by Egli and Brack-mann in Bonn in the early 1970s, that represented a milestone in German haemophilia therapy. Epidemiologic patient data from the two selected time points, 1980 and 2009, are evaluated to illustrate the change in the composition of the patient clientele. In 1980 a total of 639 patients were treated at the Bonn Haemophilia Center. 529 patients exhibited a severe form and 110 a non-severe form of the respective clotting disorder. In 2009 the Bonn Haemophilia Center took care for a total of 837 patients. There were 445 patients who suffered from a severe form of the considered clotting disorder while 392 showed a non-severe course. The number of less severely affected patients has increased significantly in 2009. Patients in 1980 were predominantly suffering from a severe form and most had to travel more than 150 km from their homes to the treatment center. In 2009 the number of patients living a medium-long distance from the care provider has significantly increased while the number of patients living more than 150km from the center has decreased. Comparing 2009 to 1980 a growth of the center’s regional character becomes apparent, especially when patient age and severity of the coagulation disorder are taken into consideration. The regional character was more strongly pronounced with milder disease severity and lower patient age. Due to the existence of well established primary haemophilia care in CCCs in Germany, the trend for the recent years is that the proportion of young patients that choose haemophilia care providers closer to their homes is increasing.

The Immunological Properties of Factor VIII

1966 ◽  
Vol 16 (03/04) ◽  
pp. 559-573 ◽  
Author(s):  
L Uszyński
Keyword(s):  
Factor Viii ◽  
Inhibitory Activity ◽  
Hemophilia A ◽  
Severe Form ◽  
Molecular Defect ◽  
Bovine Plasma ◽  
Human Factor Viii ◽  
Antigenic Properties ◽  
Coagulation Tests ◽  
Normal Human

SummaryRabbits immunized against human AHG fibrinogen-free preparations, were shown to produce anti-AHG antibodies. The inhibitory activity of these antibodies was tested by thromboplastin generation test, thrombelastography, and the specific anti-AHG antibodies neutralization test. The latter test permitted quantitative determination of antigenic form of factor VIII. The inhibitory activity of anti-FI-O-Ta serum resulted exclusively from the anti-AHG antibodies which in coagulation tests behaved like circulating anticoagulants directed against factor VIII.The anti-AHG antibodies were neutralizable by normal human serum or plasma even contained only trace of AHG activity after storage. There was no antigenic form of factor VIII in the severely affected patients with hemophilia A, von Willebrand’s disease nor in the normal plasma adsorbed on bentonite. The presented results suggest a molecular defect of factor VIII in patients with hemophilia A. The severe form of this disease depends, probably, on a major impairment of AHG biosynthesis, leading to changes in the antigenic properties of the molecule. The AHG from rabbit, porcine and bovine plasma respectively did not neutralize the anti-AHG antibodies formed in rabbits immunized against human factor VIII preparations.

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