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    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.
    Mol Cell Biol 2018 Mar 26. Epub 2018 Mar 26.
    Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX
    TIN2 is central to the shelterin complex, linking the telomeric proteins TRF1 and TRF2 with TPP1/POT1. Mutations in , 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. Read More

    The age of heterozygous mutant parents influences the adult phenotype of their offspring irrespective of genotype in zebrafish.
    Wellcome Open Res 2017 4;2:77. Epub 2017 Sep 4.
    Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
    Background: Mutations in proteins involved in telomere maintenance lead to a range of human diseases, including dyskeratosis congenita, idiopathic pulmonary fibrosis and cancer. Telomerase functions to add telomeric repeats back onto the ends of chromosomes, however non-canonical roles of components of telomerase have recently been suggested.

    Methods: Here we use a zebrafish telomerase mutant which harbours a nonsense mutation in to investigate the adult phenotypes of fish derived from heterozygous parents of different ages. Read More

    The role of telomere binding molecules for normal and abnormal hematopoiesis.
    Int J Hematol 2018 Mar 17. Epub 2018 Mar 17.
    Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
    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. Read More

    Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over-extension.
    Nucleic Acids Res 2018 Mar 7. Epub 2018 Mar 7.
    Institut Curie, PSL Research University, Sorbonne Universités, CNRS UMR3244 Telomere and cancer lab, 75005 Paris, France.
    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). Read More

    A unique homozygous WRAP53 Arg298Trp mutation underlies dyskeratosis congenita in a Chinese Han family.
    BMC Med Genet 2018 Mar 7;19(1):40. Epub 2018 Mar 7.
    State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China.
    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. Read More

    Cytomegalovirus Retinitis as a Presenting Feature of Multisystem Disorder: Dyskeratosis Congenita.
    Middle East Afr J Ophthalmol 2017 Oct-Dec;24(4):219-221
    Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.
    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 "Dyskeratosis congenita. Read More

    Heterozygous variants in bone marrow failure and myeloid neoplasms.
    Blood Adv 2018 Jan 4;2(1):36-48. Epub 2018 Jan 4.
    Department of Haematological Medicine, King's College Hospital, London, United Kingdom.
    Biallelic germline mutations in (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic 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). Read More

    Treatment of inherited bone marrow failure syndromes beyond transplantation.
    Hematology Am Soc Hematol Educ Program 2017 Dec;2017(1):96-101
    Department of Internal Medicine, University of São Paulo at Ribeirão Preto School of Medicine, Ribeirão Preto, SP, Brazil.
    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. Read More

    Inherited bone marrow failure syndromes: considerations pre- and posttransplant.
    Hematology Am Soc Hematol Educ Program 2017 Dec;2017(1):88-95
    Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
    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. Read More

    Inherited SHQ1 mutations impair interaction with NAP57/dyskerin, a major target in dyskeratosis congenita.
    Mol Genet Genomic Med 2017 11 15;5(6):805-808. Epub 2017 Aug 15.
    Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, 10461.
    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. Read More

    Inherited bone marrow failure syndromes: considerations pre- and posttransplant.
    Blood 2017 11;130(21):2257-2264
    Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
    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. Read More

    Unilateral Coats'-like disease and an intragenic deletion in the TERC gene: A case report.
    Ophthalmic Genet 2018 Apr 21;39(2):247-250. Epub 2017 Nov 21.
    c Department of Human Genetics , University Hospitals of Leuven , Leuven , Belgium.
    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. Read More

    Clinical heterogeneity in a family with mutation, dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome in first cousins.
    Pediatr Rep 2017 Oct 6;9(3):7301. Epub 2017 Oct 6.
    Unit of Pediatrics, Castelli Hospital, Verbania.
    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. Read More

    Acute telomerase components depletion triggers oxidative stress as an early event previous to telomeric shortening.
    Redox Biol 2018 Apr 7;14:398-408. Epub 2017 Oct 7.
    Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain. Electronic address:
    Loss of function of dyskerin (DKC1), NOP10 and TIN2 are responsible for different inheritance patterns of Dyskeratosis congenita (DC; ORPHA1775). They are key components of telomerase (DKC1 and NOP10) and shelterin (TIN2), and play an important role in telomere homeostasis. They participate in several fundamental cellular processes by contributing to Dyskeratosis congenita through mechanisms that are not fully understood. Read More

    Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up.
    Haematologica 2018 Jan 19;103(1):30-39. Epub 2017 Oct 19.
    Biostatistics Branches, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
    The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. Read More

    A new role for human dyskerin in vesicular trafficking.
    FEBS Open Bio 2017 Oct 12;7(10):1453-1468. Epub 2017 Sep 12.
    Department of BiologyUniversity of Naples 'Federico II'NapoliItaly.
    Dyskerin is an essential, conserved, multifunctional protein found in the nucleolus, whose loss of function causes the rare genetic diseases X-linked dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. To further investigate the wide range of dyskerin's biological roles, we set up stable cell lines able to trigger inducible protein knockdown and allow a detailed analysis of the cascade of events occurring within a short time frame. We report that dyskerin depletion quickly induces cytoskeleton remodeling and significant alterations in endocytic Ras-related protein Rab-5A/Rab11 trafficking. Read More

    Successful Second Unrelated Donor Hematopoietic Stem Cell Transplant in a Patient With Dyskeratosis Congenital After First Graft Rejection.
    Exp Clin Transplant 2017 Sep 30. Epub 2017 Sep 30.
    Stem Cell Transplantation Unit, Department of Pediatric Hematology and Oncology, Istituto Giannina Gaslini, Genoa, Italy.
    Dyskeratosis congenita is a rare congenital telomeropathy characterized by cutaneous and nail dystrophy, oral leukoplakia, and bone marrow failure. Pulmonary fibrosis and cancers are late manifestations. Allogeneic hematopoietic stem cell transplant represents the only cure for those with bone marrow failure with this disease, but outcomes reported are overall poor, with organ toxicities, graft failure, and graft-versus-host disease as main issues. Read More

    Malignant transformation of oral leukoplakia in a patient with dyskeratosis congenita.
    Oral Surg Oral Med Oral Pathol Oral Radiol 2017 Oct 12;124(4):e239-e242. Epub 2017 Aug 12.
    Department of Dermatology, Walter Reed National Military Medical Center, Bethesda, MD, USA.
    Dyskeratosis congenita (DC) is a rare, inherited, bone marrow failure syndrome caused by premature telomere shortening. The classic mucocutaneous triad of clinical features comprises reticulated skin pigmentation, nail dysplasia, and oral leukoplakia. Multiple somatic features, including bone marrow failure, pulmonary fibrosis, and liver disease, are also common. Read More

    Revesz syndrome masquerading as traumatic retinal detachment.
    J AAPOS 2017 Oct 1;21(5):422-425.e1. Epub 2017 Sep 1.
    Department of Ophthalmology, University of California, San Francisco. Electronic address:
    A 13-month-old boy with mild hemophilia A presented for strabismus evaluation and was found to have retinal hemorrhages in the right eye, left exotropia, and left total retinal detachment. These findings were attributed to trauma and hemophilia A. Routine blood work for hemophilia A subsequently showed pancytopenia. Read More

    Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome.
    Clin Epigenetics 2017 30;9:92. Epub 2017 Aug 30.
    CRIIS (Interdisciplinary, Interdepartmental and Specialistic Reference Center for Early Diagnosis of Scleroderma, Treatment of Sclerodermic Ulcers and Videocapillaroscopy), Sandro Pertini Hospital, Rome, Italy.
    Background: Werner syndrome is a progeroid disorder characterized by premature age-related phenotypes. Although it is well established that autosomal recessive mutations in the WRN gene is responsible for Werner syndrome, the molecular alterations that lead to disease phenotype remain still unidentified.

    Results: To address whether epigenetic changes can be associated with Werner syndrome phenotype, we analysed genome-wide DNA methylation profile using the Infinium MethylationEPIC BeadChip in the whole blood from three patients affected by Werner syndrome compared with three age- and sex-matched healthy controls. Read More

    Treatment of Refractory Infantile Hemangiomas and Pulmonary Hypertension With Sirolimus in a Pediatric Patient.
    J Pediatr Hematol Oncol 2017 Oct;39(7):e391-e393
    Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI.
    Infantile hemangioma is a benign vascular neoplasm that spontaneously involutes over time. Management, when needed, consists of medications, laser treatment and surgical excision. We describe a 3-year-old girl who presented shortly after birth with diffuse cutaneous hemangiomas, hepatosplenomegaly with liver lesions, anemia, and acute heart failure. Read More

    Comment on: Acquired monosomy 7 myelodysplastic syndrome in a child with clinical features of dyskeratosis congenita and IMAGe association.
    Pediatr Blood Cancer 2018 Jan 17;65(1). Epub 2017 Aug 17.
    Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

    Correlation of Leukocyte Telomere Length Measurement Methods in Patients with Dyskeratosis Congenita and in Their Unaffected Relatives.
    Int J Mol Sci 2017 Aug 13;18(8). Epub 2017 Aug 13.
    Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    Several methods have been employed to measure telomere length (TL) in human studies. It has been difficult to directly compare the results from these studies because of differences in the laboratory techniques and output parameters. We compared TL measurements (TLMs) by the three most commonly used methods, quantitative polymerase chain reaction (qPCR), flow cytometry with fluorescence in situ hybridization (flow FISH) and Southern blot, in a cohort of patients with the telomere biology disorder dyskeratosis congenita (DC) and in their unaffected relatives (controls). Read More

    Pregnancy outcomes in mothers of offspring with inherited bone marrow failure syndromes.
    Pediatr Blood Cancer 2018 Jan 12;65(1). Epub 2017 Aug 12.
    Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Rockville, Maryland.
    Background: Children with inherited bone marrow failure syndromes (IBMFSs) may be symptomatic in utero, resulting in maternal and fetal problems during the pregnancy. Subsequent pregnancies by their mothers should be considered "high risk".

    Methods: We retrospectively analyzed outcomes of 575 pregnancies in 165 unaffected mothers of offspring with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS) for events noted during pregnancy, labor, and delivery. Read More

    PARN Modulates Y RNA Stability and Its 3'-End Formation.
    Mol Cell Biol 2017 Oct 26;37(20). Epub 2017 Sep 26.
    Department of Chemistry and Biochemistry and Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado, USA
    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. Read More

    p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita.
    Stem Cell Reports 2017 Aug 27;9(2):409-418. Epub 2017 Jul 27.
    Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address:
    Dyskeratosis congenita (DC) is a bone marrow failure syndrome associated with telomere dysfunction. The progression and molecular determinants of hematopoietic failure in DC remain poorly understood. Here, we use the directed differentiation of human embryonic stem cells harboring clinically relevant mutations in telomerase to understand the consequences of DC-associated mutations on the primitive and definitive hematopoietic programs. Read More

    Hematopoietic cell transplantation in Fanconi anemia and dyskeratosis congenita: A minireview.
    Hematol Oncol Stem Cell Ther 2017 Dec 15;10(4):285-289. Epub 2017 Jun 15.
    Pediatric Hematology Oncology Section of Pediatric Stem Cell Transplant, Department of Pediatric Hematology Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Electronic address:
    Bone marrow failure syndrome is an epithet of bone marrow failure (all or single-cell lineage) that is attributable to an underlying genetic aberration usually with a constellation of somatic abnormalities. Multiple inheritance patterns have been described in these disorders; many are transmitted in an autosomal recessive pattern, which may consequently lead to a higher prevalence of such illnesses in homogeneous societies such as Saudi Arabia, where consanguineous marriages are not uncommon. At King Faisal Specialist Hospital and Research Center, the most common entity referred for allogeneic hematopoietic cell transplantation (HCT) is Fanconi anemia, followed by pure red aplasia, and, less commonly, dyskeratosis congenita, congenital neutropenia, and others. Read More

    Classical inherited bone marrow failure syndromes with high risk for myelodysplastic syndrome and acute myelogenous leukemia.
    Semin Hematol 2017 04 7;54(2):105-114. Epub 2017 Apr 7.
    Haematology Unit, Istituto Giannina Gaslini, Genoa, Italy.
    The inherited marrow failure syndromes (IBMFS) are a heterogeneous group of diseases characterized by failure in the production of one or more blood lineage. The clinical manifestations of the IBMFS vary according to the type and number of blood cell lines involved, including different combinations of anemia, leukopenia, and thrombocytopenia. In some IBMFS, systemic non-hematologic manifestations, including congenital malformations, mucocutaneous abnormalities, developmental delay, and other medical complications, may be present. Read More

    Disease-specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes.
    Ann Hematol 2017 Aug 16;96(8):1389-1397. Epub 2017 Jun 16.
    Shanghai Children's Medical Center, Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
    Hematopoietic stem cell transplantation (HSCT) using an optimized conditioning regimen is essential for the long-term survival of patients with inherited bone marrow failure syndromes (IBMFS). We report HSCT in 24 children with Fanconi anemia (FA, n = 12), Diamond-Blackfan anemia (DBA, n = 7), and dyskeratosis congenita (DC, n = 5) from a single HSCT center. The graft source was peripheral blood stem cells (n = 19) or cord blood stem cells (n = 5). Read More

    Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders.
    Clin Cancer Res 2017 Jun;23(11):e23-e31
    National Cancer Institute, Rockville, Maryland.
    DNA repair syndromes are heterogeneous disorders caused by pathogenic variants in genes encoding proteins key in DNA replication and/or the cellular response to DNA damage. The majority of these syndromes are inherited in an autosomal-recessive manner, but autosomal-dominant and X-linked recessive disorders also exist. The clinical features of patients with DNA repair syndromes are highly varied and dependent on the underlying genetic cause. Read More

    Allogeneic Hematopoietic Cell Transplantation for Dyskeratosis Congenita: A Report of 3 Cases.
    J Pediatr Hematol Oncol 2017 Oct;39(7):e394-e398
    *Department of Pediatrics, Kyoto City Hospital †Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
    Although bone marrow failure in patients with dyskeratosis congenita (DKC) can be successfully treated with allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced intensity conditioning (RIC) regimen, the outcome of nonhematological disorders in patients with DKC treated with allo-HCT using RIC has not been fully elucidated. Here, we describe the clinical course of nonhematological disorders after allo-HCT with RIC in 3 consecutive patients with DKC. Allo-HCT with RIC was feasible in all cases; however, patient 1 developed lethal pulmonary disease and patient 2 experienced progression of hepatic fibrosis. Read More

    Late Effects Screening Guidelines after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement From the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects After Pediatric HCT.
    Biol Blood Marrow Transplant 2017 Sep 19;23(9):1422-1428. Epub 2017 May 19.
    Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
    Patients with inherited bone marrow failure syndromes (IBMFS), such as Fanconi anemia (FA), dyskeratosis congenita (DC), or Diamond Blackfan anemia (DBA), can have hematologic manifestations cured through hematopoietic cell transplantation (HCT). Subsequent late effects seen in these patients arise from a combination of the underlying disease, the pre-HCT therapy, and the HCT process. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium on late effects screening and recommendations following allogeneic hematopoietic cell transplantation for immune deficiency and nonmalignant hematologic diseases held in Minneapolis, Minnesota in May 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. Read More

    Clinical and Molecular Heterogeneity of RTEL1 Deficiency.
    Front Immunol 2017 1;8:449. Epub 2017 May 1.
    Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
    Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. Read More

    Is the Hepatic Factor a miRNA that Maintains the Integrity of Pulmonary Microvasculature by Inhibiting the Vascular Endothelial Growth Factor?
    Curr Cardiol Rev 2017 ;13(3):244-250
    Congenital Heart Center, Helen DeVos Children's Hospital, 100 Michigan NE (MC248), Grand Rapids, MI 49503, United States.
    Background: The "hepatic factor," a molecule or group of molecules present in the hepatic venous blood, essential for the prevention of the development of pulmonary arteriovenous malformations (PAVMs) and right-to-left shunting has been a conceptual enigma in the understanding of many related conditions.

    Methods: Patients with various forms of liver diseases including acute hepatic failure, and others with normal hepatic function like hereditary hemorrhagic telangiectasia (HHT), inflammatory and parasitic disorders, cardiogenic hepatopulmonary syndrome (cHPS) and skin disorders like Dyskeratosis congenita are all known to cause PAVMs. Over a period of the last two decades our understanding of the pathogenesis of PAVMs has changed, but the mechanisms are still not clearly understood. Read More

    Bone mineral density in patients with inherited bone marrow failure syndromes.
    Pediatr Res 2017 Sep 31;82(3):458-464. Epub 2017 May 31.
    Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.
    BackgroundPatients with inherited bone marrow failure syndromes (IBMFS) may have several risk factors for low bone mineral density (BMD). We aimed to evaluate the prevalence of low BMD in IBMFS and determine the associated risk factors.MethodsPatients with IBMFS with at least one dual-energy X-ray absorptiometry (DXA) scan were evaluated. Read More

    Telomeres in health and disease.
    J Oral Maxillofac Pathol 2017 Jan-Apr;21(1):87-91
    Department of Oral and Maxillofacial Pathology, MMCDSR, MM University, Ambala, Haryana, India.
    Telomeres are repetitive ribonucleoprotein complexes present at ends of chromosomes. To synthesize this manuscript, a thorough literature search was done using PubMed, MEDLINE and Cochrane review for English-language literature and data available from the period of 2005-2016 were analyzed for manuscript writing. Telomeres help in maintaining the cellular health, inbuilt cellular mechanisms, metabolism and normal cell cycle. Read More

    Systematic Computational Identification of Variants That Activate Exonic and Intronic Cryptic Splice Sites.
    Am J Hum Genet 2017 May;100(5):751-765
    McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:
    We developed a variant-annotation method that combines sequence-based machine-learning classification with a context-dependent algorithm for selecting splice variants. Our approach is distinctive in that it compares the splice potential of a sequence bearing a variant with the splice potential of the reference sequence. After training, classification accurately identified 168 of 180 (93. Read More

    [Recurrent pulmonary infection and oral mucosal ulcer].
    Zhongguo Dang Dai Er Ke Za Zhi 2017 Apr;19(4):452-457
    Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China.
    An 8-year-old girl who had experienced intermittent cough and fever over a 3 year period, was admitted after experiencing a recurrence for one month. One year ago the patient experienced a recurrent oral mucosal ulcer. Physical examination showed vitiligo in the skin of the upper right back. Read More

    Poly(A)-specific ribonuclease is a nuclear ribosome biogenesis factor involved in human 18S rRNA maturation.
    Nucleic Acids Res 2017 Jun;45(11):6822-6836
    Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31000 Toulouse, France.
    The poly-A specific ribonuclease (PARN), initially characterized for its role in mRNA catabolism, supports the processing of different types of non-coding RNAs including telomerase RNA. Mutations in PARN are linked to dyskeratosis congenita and pulmonary fibrosis. Here, we show that PARN is part of the enzymatic machinery that matures the human 18S ribosomal RNA (rRNA). Read More

    Mutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche.
    Nat Commun 2017 Mar 17;8:14766. Epub 2017 Mar 17.
    Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
    Critical telomere shortening (for example, secondary to partial telomerase deficiency in the rare disease dyskeratosis congenita) causes tissue pathology, but underlying mechanisms are not fully understood. Mice lacking telomerase (for example, mTR telomerase RNA template mutants) provide a model for investigating pathogenesis. In such mice, after several generations of telomerase deficiency telomeres shorten to the point of uncapping, causing defects most pronounced in high-turnover tissues including intestinal epithelium. Read More

    Telomere-driven diseases and telomere-targeting therapies.
    J Cell Biol 2017 04 2;216(4):875-887. Epub 2017 Mar 2.
    Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid E-28029, Spain
    Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Telomere shortening is proposed to be a primary molecular cause of aging. Short telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, and trigger the development of age-associated diseases. Read More

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