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1.
Hum Mol Genet ; 29(6): 907-922, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31985013

RESUMO

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.


Assuntos
Disceratose Congênita/patologia , Retardo do Crescimento Fetal/patologia , Deficiência Intelectual/patologia , Microcefalia/patologia , Mutação , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Fibrose Pulmonar/patologia , RNA Ribossômico/biossíntese , Ribonucleoproteínas Nucleares Pequenas/deficiência , Ribonucleoproteínas Nucleares Pequenas/genética , Idoso , Sequência de Aminoácidos , Disceratose Congênita/etiologia , Feminino , Retardo do Crescimento Fetal/etiologia , Humanos , Recém-Nascido , Deficiência Intelectual/etiologia , Masculino , Microcefalia/etiologia , Pessoa de Meia-Idade , Proteínas Nucleares/química , Linhagem , Regiões Promotoras Genéticas , Fibrose Pulmonar/etiologia , Ribonucleoproteínas Nucleares Pequenas/química , Homologia de Sequência , Telomerase/genética , Transcrição Gênica
2.
Am J Med Genet A ; 176(6): 1432-1437, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29696773

RESUMO

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. Family history was not available but genome-wide genotyping was consistent with consanguinity. Whole exome sequencing identified 82 variants of interest in 80 genes based on the following criteria: homozygous, <0.1% minor allele frequency in public and in-house databases, nonsynonymous, and predicted deleterious by multiple in silico prediction programs. Six genes were identified likely contributory to the clinical presentation. The cause of DC is likely due to homozygous splice site variants in regulator of telomere elongation helicase 1, a known DC and telomere biology gene. A homozygous, missense variant in tryptophan hydroxylase 1 may be clinically important as this gene encodes the rate limiting step in serotonin biosynthesis, a biologic pathway connected with mood disorders. Four additional genes (SCN4A, LRP4, GDAP1L1, and SPTBN5) had rare, missense homozygous variants that we speculate may contribute to portions of the clinical phenotype. This case illustrates the value of conducting detailed clinical and genomic evaluations on rare patients in order to identify new areas of research into the functional consequences of rare variants and their contribution to human disease.


Assuntos
DNA Helicases/genética , Disceratose Congênita/etiologia , Transtornos do Humor/etiologia , Triptofano Hidroxilase/genética , Adolescente , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/genética , Disceratose Congênita/genética , Homozigoto , Humanos , Hipotireoidismo/etiologia , Hipotireoidismo/genética , Masculino , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/genética , Fenótipo , Sequenciamento Completo do Genoma , Adulto Jovem
3.
Curr Opin Hematol ; 23(6): 501-507, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27607446

RESUMO

PURPOSE OF REVIEW: Dyskeratosis congenita is an inherited bone marrow failure syndrome caused by defects in telomere maintenance. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure because of dyskeratosis congenita. The present review summarizes the literature with respect to the diagnosis and treatment of patients with dyskeratosis congenita who received HSCT, and discusses the recent progress in the management of dyskeratosis congenita. RECENT FINDINGS: The recent systematic review of the literature showed poor long-term outcome, with 10-year survival estimates of only 23% in 109 patients with dyskeratosis congenita who received HSCT. Multivariate analysis identified age greater than 20 years at HSCT, HSCT before 2000, and alternative donor source to be poor prognostic markers. HSCT for dyskeratosis congenita is characterized by a marked decline in long-term survival because of late deaths from pulmonary complications. However, a prospective study using danazol showed promising results in gain in telomere length and hematologic responses. SUMMARY: A recent prospective study may support the recommendation that HSCT is not indicated for patients with dyskeratosis congenita; instead, they should receive androgen, particularly danazol, as a first-line therapy. Another option may be routine use of androgen after HSCT for the prophylaxis of pulmonary fibrosis.


Assuntos
Disceratose Congênita/terapia , Transplante de Células-Tronco Hematopoéticas , Terapia Combinada , Gerenciamento Clínico , Disceratose Congênita/diagnóstico , Disceratose Congênita/etiologia , Disceratose Congênita/mortalidade , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Doadores de Tecidos , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento
4.
PLoS Genet ; 9(8): e1003695, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24009516

RESUMO

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.


Assuntos
DNA Helicases/genética , Disceratose Congênita/genética , Disceratose Congênita/patologia , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Síndromes de Imunodeficiência/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Microcefalia/genética , Microcefalia/patologia , Adulto , Disceratose Congênita/etiologia , Feminino , Retardo do Crescimento Fetal/etiologia , Genes Recessivos , Mutação em Linhagem Germinativa , Homozigoto , Humanos , Síndromes de Imunodeficiência/genética , Deficiência Intelectual/etiologia , Judeus , Microcefalia/etiologia , Dados de Sequência Molecular , Mutação , Fenótipo , Telomerase/genética , Telômero/genética
5.
Curr Opin Genet Dev ; 23(5): 526-33, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23993228

RESUMO

A unique characteristic of tissue stem cells is the ability to self-renew, a process that enables the life-long maintenance of many organs. Stem cell self-renewal is dependent in part on the synthesis of telomere repeats by the enzyme telomerase. Defects in telomerase and in genes in the telomere maintenance pathway result in diverse disease states, including dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, liver cirrhosis and cancer. Many of these disease states share a tissue failure phenotype, such as loss of bone marrow cells or failure of pulmonary epithelium, suggesting that stem cell dysfunction is a common pathophysiological mechanism underlying these telomere diseases. Studies of telomere diseases in undifferentiated iPS cells have provided a quantitative relationship between the magnitude of biochemical defects in the telomerase pathway and disease severity in patients, thereby establishing a clear correlation between genotype and phenotype in telomere disease states. Modeling telomere diseases in iPS cells has also revealed diverse underlying disease mechanisms, including reduced telomerase catalytic activity, diminished assembly of the telomerase holoenzyme and impaired trafficking of the enzyme within the nucleus. These studies highlight the need for therapies tailored to the underlying biochemical defect in each class of patients.


Assuntos
Divisão Celular/genética , Células-Tronco Pluripotentes Induzidas/citologia , Telomerase/genética , Telômero/genética , Anemia Aplástica/etiologia , Anemia Aplástica/genética , Anemia Aplástica/patologia , Disceratose Congênita/etiologia , Disceratose Congênita/genética , Disceratose Congênita/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Mutação , Neoplasias/etiologia , Neoplasias/genética , Neoplasias/patologia , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia
6.
Transl Res ; 162(6): 353-63, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23732052

RESUMO

Telomeres are DNA-protein structures that form a protective cap on chromosome ends. As such, they prevent the natural ends of linear chromosomes from being subjected to DNA repair activities that would result in telomere fusion, degradation, or recombination. Both the DNA and protein components of the telomere are required for this essential function, because insufficient telomeric DNA length, loss of the terminal telomeric DNA structure, or deficiency of key telomere-associated factors may elicit a DNA damage response and result in cellular senescence or apoptosis. In the setting of failed checkpoint mechanisms, such DNA-protein defects can also lead to genomic instability through telomere fusions or recombination. Thus, as shown in both model systems and in humans, defects in telomere biology are implicated in cellular and organismal aging as well as in tumorigenesis. Bone marrow failure and malignancy are 2 life-threatening disease manifestations in the inherited telomere biology disorder dyskeratosis congenita. We provide an overview of basic telomere structure and maintenance. We outline the telomere biology defects observed in dyskeratosis congenita, focusing on recent discoveries in this field. Last, we review the evidence of how telomere biology may impact sporadic aplastic anemia and the risk for various cancers.


Assuntos
Anemia Aplástica/etiologia , Disceratose Congênita/etiologia , Neoplasias/etiologia , Encurtamento do Telômero , Envelhecimento/genética , Envelhecimento/fisiologia , Humanos , Mutação , Fatores de Risco , Complexo Shelterina , Telomerase/genética , Telomerase/fisiologia , Encurtamento do Telômero/genética , Encurtamento do Telômero/fisiologia , Proteínas de Ligação a Telômeros , Pesquisa Translacional Biomédica
7.
Blood ; 120(15): 2990-3000, 2012 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-22932806

RESUMO

TRF1 is part of the shelterin complex, which binds telomeres and it is essential for their protection. Ablation of TRF1 induces sister telomere fusions and aberrant numbers of telomeric signals associated with telomere fragility. Dyskeratosis congenita is characterized by a mucocutaneous triad, bone marrow failure (BMF), and presence of short telomeres because of mutations in telomerase. A subset of patients, however, show mutations in the shelterin component TIN2, a TRF1-interacting protein, presenting a more severe phenotype and presence of very short telomeres despite normal telomerase activity. Allelic variations in TRF1 have been found associated with BMF. To address a possible role for TRF1 dysfunction in BMF, here we generated a mouse model with conditional TRF1 deletion in the hematopoietic system. Chronic TRF1 deletion results in increased DNA damage and cellular senescence, but not increased apoptosis, in BM progenitor cells, leading to severe aplasia. Importantly, increased compensatory proliferation of BM stem cells is associated with rapid telomere shortening and further increase in senescent cells in vivo, providing a mechanism for the very short telomeres of human patients with mutations in the shelterin TIN2. Together, these results represent proof of principle that mutations in TRF1 lead to the main clinical features of BMF.


Assuntos
Medula Óssea/patologia , Senescência Celular , Modelos Animais de Doenças , Disceratose Congênita/etiologia , Sistema Hematopoético/patologia , Hemoglobinúria Paroxística/etiologia , Proteína 1 de Ligação a Repetições Teloméricas/fisiologia , Anemia Aplástica , Animais , Apoptose , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Transplante de Medula Óssea , Proliferação de Células , Ensaio de Unidades Formadoras de Colônias , Dano ao DNA , Disceratose Congênita/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Hemoglobinúria Paroxística/mortalidade , Hemoglobinúria Paroxística/patologia , Humanos , Integrases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mutação/genética , Pancitopenia/etiologia , Pancitopenia/metabolismo , Pancitopenia/patologia , Células-Tronco/patologia , Taxa de Sobrevida , Telômero/genética , Proteínas de Ligação a Telômeros/genética
8.
Med Sci (Paris) ; 28(6-7): 618-24, 2012.
Artigo em Francês | MEDLINE | ID: mdl-22805138

RESUMO

Telomeres are nucleoprotein structures at the end of linear chromosomes. Their length, structure, and integrity are regulated by the telomerase complex, the shelterins and components of the DNA damage response. In human subjects, defects in telomere maintenance are responsible for Dyskeratosis Congenita (DC), a rare genetic disorder characterized by aplastic anaemia, premature aging and predisposition to cancer. Recent data from the study of patients with Hoyeraal-Hreidarsson syndrome, a severe variant of DC, demonstrate the great molecular heterogeneity of this disease. While most cases of DC are associated with defects in factors involved in telomere length regulation, some severe forms of the disease seem to be rather associated with defects in telomere replication and protection.


Assuntos
Disceratose Congênita/genética , Telômero/fisiologia , Replicação do DNA/genética , Replicação do DNA/fisiologia , Disceratose Congênita/diagnóstico , Disceratose Congênita/etiologia , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Microcefalia/diagnóstico , Microcefalia/genética , Modelos Biológicos , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/fisiologia , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo
9.
BMJ Case Rep ; 20102010 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-22798484

RESUMO

Dyskeratosis congenita (DC) is a rare disease characterised by bone marrow failure and skin manifestations. Patients with DC may exhibit short stature that is not usually related to growth hormone (GH) deficiency. Replacement treatment with GH should be done cautiously as it can predispose to haematological malignancy. We present a 10-year-old boy with DC and GH deficiency.


Assuntos
Disceratose Congênita/diagnóstico , Transplante de Medula Óssea , Proteínas de Ciclo Celular/genética , Criança , Disceratose Congênita/etiologia , Disceratose Congênita/genética , Disceratose Congênita/cirurgia , Heterozigoto , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética
10.
Gene ; 403(1-2): 194-203, 2007 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17888589

RESUMO

Some popular ideas about translational regulation in eukaryotes have been recognized recently as mistakes. One example is the rejection of a long-standing idea about involvement of S6 kinase in translation of ribosomal proteins. Unfortunately, new proposals about how S6 kinase might regulate translation are based on evidence that is no better than the old. Recent findings have also forced rejection of some popular ideas about the function of sequences at the 3' end of viral mRNAs and rejection of some ideas about internal ribosome entry sequences (IRESs). One long-held belief was that tissue-specific translation via an IRES underlies the neurotropism of poliovirus and the attenuation of Sabin vaccine strains. Older experiments that appeared to support this belief and recent experiments that refute it are discussed. The hypothesis that dyskeratosis congenita is caused by a defect in IRES-mediated translation is probably another mistaken idea. The supporting evidence, such as it is, comes from a mouse model of the disease and is contradicted by studies carried out with cells from affected patients. The growing use of IRESs as tools to study other questions about translation is discussed and lamented. The inefficient function of IRESs (if they are IRESs) promotes misunderstandings. I explain again why it is not valid to invoke a special mechanism of initiation based on the finding that edeine (at very low concentrations) does not inhibit the translation of a putative IRES from cricket paralysis virus. I explain why new assays, devised to rule out splicing in tests with dicistronic vectors, are not valid and why experiments with IRESs are not a good way to investigate the mechanism whereby microRNAs inhibit translation.


Assuntos
Modelos Biológicos , Biossíntese de Proteínas , Animais , Disceratose Congênita/etiologia , Edeína/farmacologia , Células Eucarióticas , Humanos , MicroRNAs/genética , Inibidores da Síntese de Ácido Nucleico/farmacologia , Iniciação Traducional da Cadeia Peptídica , Poliovirus/genética , Poliovirus/patogenicidade , Poliovirus/fisiologia , Vacina Antipólio Oral , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/química , RNA Viral/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sequências Reguladoras de Ácido Nucleico/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Ribossomos/metabolismo , Replicação Viral
12.
Proc Natl Acad Sci U S A ; 102(44): 15960-4, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16247010

RESUMO

Dyskeratosis congenita is a rare inherited disorder characterized by abnormal skin manifestations. Morbidity and mortality from this disease is usually due to bone marrow failure, but idiopathic pulmonary fibrosis and an increased cancer predisposition also occur. Families with autosomal dominant dyskeratosis congenita display anticipation and have mutations in the telomerase RNA gene. We identified a three-generation pedigree with autosomal dominant dyskeratosis congenita, anticipation, and telomere shortening. We show that a null mutation in motif D of the reverse transcriptase domain of the protein component of telomerase, hTERT, is associated with this phenotype. This mutation leads to haploinsufficiency of telomerase, and telomere shortening occurs despite the presence of telomerase. This finding emphasizes the importance of telomere maintenance and telomerase dosage for maintaining tissue proliferative capacity and has relevance for understanding mechanisms of age-related changes.


Assuntos
Antecipação Genética , Proteínas de Ligação a DNA/genética , Disceratose Congênita/genética , Genes Dominantes/genética , Haplótipos , Telomerase/genética , Adolescente , Adulto , Proliferação de Células , Criança , Pré-Escolar , Proteínas de Ligação a DNA/deficiência , Disceratose Congênita/etiologia , Saúde da Família , Feminino , Dosagem de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Telomerase/deficiência , Telômero/ultraestrutura
13.
Blood Cells Mol Dis ; 34(3): 257-63, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15885610

RESUMO

Human telomerase has two core components, the RNA molecule (TERC) that provides the template for telomere repeat elongation and a reverse transcriptase (TERT) that is responsible for the addition of telomere repeats at the ends of each chromosome. Mutations in TERC have been found in the autosomal-dominant form of the inherited bone marrow failure syndrome dyskeratosis congenita and in a subset of patients with aplastic anemia and myelodysplasia. These patients have short telomeres compared to age-matched controls. These observations suggest that uncharacterised cases of dyskeratosis congenita/aplastic anemia may have mutations in TERT or other molecules that associate with TERC in the telomerase complex. We have therefore screened the TERT gene for mutation by denaturing HPLC in 80 patients with inherited and acquired bone marrow failure (24 with dyskeratosis congenita, 36 with constitutional aplastic anemia, 13 with idiopathic aplastic anemia and 7 with other forms of bone marrow failure). 15 different TERT mutations have been identified. Of these, 5 are in flanking intron sequences, 6 are synonymous and 4 are non-synonymous (missense) substitutions in the coding sequence. These are the first natural mutations of TERT to be described and we highlight their possible pathogenic role in the development of bone marrow failure.


Assuntos
Doenças da Medula Óssea/enzimologia , Mutação , Adulto , Anemia Aplástica/enzimologia , Anemia Aplástica/etiologia , Anemia Aplástica/genética , Doenças da Medula Óssea/etiologia , Doenças da Medula Óssea/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Disceratose Congênita/enzimologia , Disceratose Congênita/etiologia , Disceratose Congênita/genética , Éxons , Feminino , Humanos , Íntrons , Masculino , Linhagem , DNA Polimerase Dirigida por RNA/genética , Telomerase/genética
14.
Acta Haematol ; 111(3): 125-31, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15034232

RESUMO

Telomeres represent the nucleoprotein tails of chromosomes that get shortened with each cell division. When the telomere length reaches a critical point, cell senescence and death occur. Telomerase is a reverse transcriptase that counteracts telomere loss by adding telomeric sequences. In patients with acquired aplastic anemia, the mean telomere length (TRF) of peripheral blood leukocytes is generally short when compared to normal controls, without it being clear whether a relationship between TRF and disease severity exists. Additionally, increased telomerase activity (TA) is found in the bone marrow mononuclear cell population (MNCs) of aplastic anemia patients, especially in the chronic form of the disease. Fanconi anemia (FA) patients generally demonstrate increased TA and short telomeres in peripheral blood MNCs, a fact attributed to the high turnover of hematopoietic progenitor cells in combination with direct breakages at telomeric sequences. Furthermore, a strong correlation has been shown between TRF and the severity of aplastic anemia, but not with FA evolution towards myelodysplastic syndrome or acute myeloblastic leukemia. In respect of dyskeratosis congenita (DC), a disease of either X-linked or autosomal dominant/recessive inheritance which is characterized by premature ageing of highly regenerative tissues, studies have been carried out in order to elucidate whether the X-linked DC is caused by a defect in ribosomal RNA processing and/or telomere maintenance. Finally, the direct genetic link established between DC pathogenesis and short telomeres may lead to the development of new therapeutic protocols for diseases characterized by short telomere length and subsequent genomic instability.


Assuntos
Anemia Aplástica/genética , Telomerase/fisiologia , Telômero/fisiologia , Anemia Aplástica/congênito , Anemia Aplástica/etiologia , Disceratose Congênita/etiologia , Disceratose Congênita/genética , Anemia de Fanconi/etiologia , Anemia de Fanconi/genética , Humanos , Telomerase/metabolismo , Telômero/metabolismo , Telômero/ultraestrutura
15.
Blood Rev ; 17(4): 217-25, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14556776

RESUMO

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome exhibiting considerable clinical and genetic heterogeneity. X-linked recessive, autosomal dominant and autosomal recessive forms are recognised. The gene mutated in X-linked DC (DKC1) encodes a highly conserved nucleolar protein called dyskerin. Dyskerin associates with the H/ACA class of small nucleolar RNAs which are important in guiding the conversion of uracil to pseudouracil in ribosomal RNA. Dyskerin also associates with the RNA component of telomerase (hTR) which is important in the maintenance of telomeres. Mutations in hTR were recently demonstrated in patients with autosomal dominant DC and in a subset of patients with aplastic anaemia (AA) but without other diagnostic features of DC. This discovery demonstrates that both DC and a subset of AA are due to a defect in telomerase. The link between DC and AA and in turn to defective telomerase suggests that treatments directed at correction of telomerase activity might benefit DC/AA patients who do not respond to conventional therapy.


Assuntos
Anemia Aplástica/genética , Disceratose Congênita/genética , RNA/genética , Telomerase/genética , Anemia Aplástica/etiologia , Proteínas de Ciclo Celular/metabolismo , Mapeamento Cromossômico , Disceratose Congênita/etiologia , Saúde da Família , Humanos , Padrões de Herança , Mutação , Proteínas Nucleares/metabolismo , RNA/metabolismo , Telomerase/metabolismo
17.
Oncogene ; 21(4): 564-79, 2002 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-11850781

RESUMO

The intent of this review is to describe what is known and unknown about telomerase in somatic cells of the human organism. First, we consider the telomerase enzyme. Human telomerase ribonucleoproteins undergo at least three stages of cellular biogenesis: accumulation, catalytic activation and recruitment to the telomere. Next, we describe the patterns of telomerase regulation in the human soma. Telomerase activation in some cell types appears to offset proliferation-dependent telomere shortening, delaying but not defeating the inherent mitotic clock. Finally, we elaborate the connection between telomerase misregulation and human disease, in the contexts of inappropriate telomerase activation and telomerase deficiency. We discuss how our current perspectives on telomerase function could be applied to improving human health.


Assuntos
Telomerase/metabolismo , Divisão Celular , Disceratose Congênita/enzimologia , Disceratose Congênita/etiologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Modelos Genéticos , Neoplasias/enzimologia , Neoplasias/etiologia , RNA/biossíntese , Telomerase/biossíntese , Telomerase/genética , Telômero/genética , Telômero/metabolismo
18.
An. bras. dermatol ; 73(1): 57-60, jan.-fev. 1998. ilus
Artigo em Inglês | LILACS | ID: lil-226525

RESUMO

Disceratose congênita é genodermatose rara com manifestaçöes hematológicas e incidência aumentada de câncer. Cerca de duzentos casos foram descritos, sendo apenas 10 porcento em pacientes do sexo feminino. É relatado o caso de paciente feminina de seis anos, sem antecedentes familiares da doença, a qual apresentou característica hiperpigmentaçäo reticular, associada a distrofia ungueal incipiente, sem leucoplasia ou envolvimento hematológico. A análise cromossômica em linfócitos cultivados mostrou 43 porcento de quebra cromossômica, 21 porcento de disjunçäo prematura de centrômero e presença de micronúcleos em 1,7 porcento das células epiteliais näo-cultivadas examinadas. Instabilidade cromossômica pode desempenhar um papel nas manifestaçöes cutâneas e hematológicas nos casos de disceratose congênitas näo-ligados ao cromossoma X


Assuntos
Humanos , Feminino , Criança , Dermatopatias Genéticas/diagnóstico , Disceratose Congênita/etiologia , Hiperpigmentação/etiologia
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