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BACKGROUND: Intramedullary abscesses are rare infections of the spinal cord. Intramedullary abscesses often have a complex presentation, making a high index of suspicion essential for prompt diagnosis and management. CASE PRESENTATION: We present two cases of intramedullary abscesses referred to and ultimately managed at our institution. Delayed diagnosis occurred in both instances due to the rarity of intramedullary abscesses and their propensity to mimic other pathologies. For both patients, prompt surgical management and the rapid institution of broad-spectrum antibiotics were critical in preventing further neurological decline. CONCLUSIONS: Although rare, it is critical to consider intramedullary abscesses on the differential for any MRI lesions that are hyperintense on T2 and peripherally enhancing on T1 post-contrast sequences, as even short delays in treatment can lead to severe neurological damage.
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Doenças da Medula Espinal , Streptococcus anginosus , Abscesso/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/tratamento farmacológicoRESUMO
Babesiosis with high-grade parasitemia is life-threatening, especially in asplenic hosts. We report an asplenic patient with parasitemia >50% who was successfully treated with prompt red blood cell apheresis and triple therapy with clindamycinâ +â azithromycinâ +â atovaquone. This regimen may be an alternative to poorly tolerated clindamycinâ +â quinine in severe cases.
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BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common of short telomere phenotypes. Familial clustering of IPF is common, but the genetic basis remains unknown in more than one-half of cases. We identified a 65-year-old man with familial IPF, short telomere length, and low telomerase RNA levels. He was diagnosed with a short telomere syndrome after developing hematologic complications post-lung transplantation, but no mutations were identified in a clinical testing pipeline. RESEARCH QUESTION: What is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient? STUDY DESIGN AND METHODS: We analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family. RESULTS: We identified a previously unreported synonymous variant c.942G>A p.K314K in DKC1, the gene encoding the dyskerin ribonucleoprotein, which is required for telomerase RNA biogenesis. The mutation created a competing de novo exonic splicing enhancer, and the misspliced product was degraded by nonsense-mediated decay causing an overall dyskerin deficiency in mutation carriers. In silico tools identified other rare silent DKC1 variants that warrant functional evaluation if found in patients with short telomere-mediated disease. INTERPRETATION: Our data point to silent mutation in telomere maintenance genes as a mechanism of familial pulmonary fibrosis. In contrast to DKC1 missense mutations, which primarily manifest in children as dyskeratosis congenita, hypomorphic mutations affecting dyskerin levels likely have a predilection to presenting in adults as pulmonary fibrosis.
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Transtornos da Insuficiência da Medula Óssea , Proteínas de Ciclo Celular/genética , Fibrose Pulmonar Idiopática , Transplante de Pulmão , Proteínas Nucleares/genética , Complicações Pós-Operatórias/diagnóstico , RNA/genética , Sepse , Telomerase/genética , Idoso , Transtornos da Insuficiência da Medula Óssea/sangue , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Evolução Fatal , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/fisiopatologia , Fibrose Pulmonar Idiopática/terapia , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/métodos , Masculino , Linhagem , Filogenia , Sepse/diagnóstico , Sepse/etiologia , Mutação Silenciosa , Neoplasias Cutâneas/patologia , Homeostase do Telômero/genética , Sequenciamento Completo do Genoma/métodosRESUMO
Short telomere syndromes manifest as familial idiopathic pulmonary fibrosis; they are the most common premature aging disorders. We used genome-wide linkage to identify heterozygous loss of function of ZCCHC8, a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with TR and was required for telomerase function. In ZCCHC8 knockout cells and in mutation carriers, genomically extended telomerase RNA (TR) accumulated at the expense of mature TR, consistent with a role for ZCCHC8 in mediating TR 3' end targeting to the nuclear RNA exosome. We generated Zcchc8-null mice and found that heterozygotes, similar to human mutation carriers, had TR insufficiency but an otherwise preserved transcriptome. In contrast, Zcchc8-/- mice developed progressive and fatal neurodevelopmental pathology with features of a ciliopathy. The Zcchc8-/- brain transcriptome was highly dysregulated, showing accumulation and 3' end misprocessing of other low-abundance RNAs, including those encoding cilia components as well as the intronless replication-dependent histones. Our data identify a novel cause of human short telomere syndromes-familial pulmonary fibrosis and uncover nuclear exosome targeting as an essential 3' end maturation mechanism that vertebrate TR shares with replication-dependent histones.
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Proteínas de Transporte/genética , Fibrose Pulmonar Idiopática/genética , Mutação com Perda de Função , Proteínas Nucleares/genética , RNA/metabolismo , Telomerase/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Linhagem Celular , Cílios/genética , Feminino , Ligação Genética , Células HCT116 , Humanos , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Transtornos do Neurodesenvolvimento/genética , Linhagem , Processamento Pós-Transcricional do RNA/genética , Encurtamento do Telômero/genéticaRESUMO
If the highly efficient C4 photosynthesis pathway could be transferred to crops with the C3 pathway there could be yield gains of up to 50%. It has been proposed that the multiple metabolic and developmental modifications associated with C4 photosynthesis are underpinned by relatively few master regulators that have allowed the evolution of C4 photosynthesis more than 60 times in flowering plants. Here we identify a component of one such regulator that consists of a pair of cis-elements located in coding sequence of multiple genes that are preferentially expressed in bundle sheath cells of C4 leaves. These motifs represent duons as they play a dual role in coding for amino acids as well as controlling the spatial patterning of gene expression associated with the C4 leaf. They act to repress transcription of C4 photosynthesis genes in mesophyll cells. These duons are also present in the C3 model Arabidopsis thaliana, and, in fact, are conserved in all land plants and even some algae that use C3 photosynthesis. C4 photosynthesis therefore appears to have coopted an ancient regulatory code to generate the spatial patterning of gene expression that is a hallmark of C4 photosynthesis. This intragenic transcriptional regulatory sequence could be exploited in the engineering of efficient photosynthesis of crops.
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Evolução Molecular , Regulação da Expressão Gênica de Plantas/fisiologia , Magnoliopsida/metabolismo , Fotossíntese/fisiologia , Folhas de Planta/metabolismo , Sequência de Bases , Magnoliopsida/genética , Mutação , Folhas de Planta/citologiaRESUMO
Telomere length (TL) predicts the onset of cellular senescence in vitro but the diagnostic utility of TL measurement in clinical settings is not fully known. We tested the value of TL measurement by flow cytometry and FISH (flowFISH) in patients with mutations in telomerase and telomere maintenance genes. TL had a discrete and reproducible normal range with definable upper and lower boundaries. While TL above the 50th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations, the lower threshold in mutation carriers was age-dependent, and adult mutation carriers often overlapped with the lowest decile of controls. The extent of telomere shortening correlated with the age at diagnosis as well as the short telomere syndrome phenotype. Extremely short TL caused bone marrow failure and immunodeficiency in children and young adults, while milder defects manifested as pulmonary fibrosis-emphysema in adults. We prospectively examined whether TL altered treatment decisions for newly diagnosed idiopathic bone marrow failure patients and found abnormally short TL enriched for patients with mutations in some inherited bone marrow failure genes, such as RUNX1, in addition to telomerase and telomere maintenance genes. The result was actionable, altering the choice of treatment regimen and/or hematopoietic stem cell donor in one-fourth of the cases (9 of 38, 24%). We conclude that TL measurement by flowFISH, when used for targeted clinical indications and in limited settings, can influence treatment decisions in ways that improve outcome.
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Enfisema Pulmonar/metabolismo , Fibrose Pulmonar/metabolismo , Encurtamento do Telômero , Telômero/metabolismo , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Hospitais/estatística & dados numéricos , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/genética , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/genética , Telomerase/genética , Telomerase/metabolismo , Telômero/química , Adulto JovemRESUMO
INTRODUCTION: Although lung cancer is generally thought to be environmentally provoked, anecdotal familial clustering has been reported, suggesting that there may be genetic susceptibility factors. We systematically tested whether germline mutations in eight candidate genes may be risk factors for lung adenocarcinoma. METHODS: We studied lung adenocarcinoma cases for which germline sequence data had been generated as part of The Cancer Genome Atlas project but had not been previously analyzed. We selected eight genes, ATM serine/threonine kinase gene (ATM), BRCA2, DNA repair associated gene (BRCA2), checkpoint kinase 2 gene (CHEK2), EGFR, parkin RBR E3 ubiquitin protein ligase gene (PARK2), telomerase reverse transcriptase gene (TERT), tumor protein p53 gene (TP53), and Yes associated protein 1 gene (YAP1), on the basis of prior anecdotal association with lung cancer or genome-wide association studies. RESULTS: Among 555 lung adenocarcinoma cases, we detected 14 pathogenic mutations in five genes; they occurred at a frequency of 2.5% and represented an OR of 66 (95% confidence interval: 33-125, p < 0.0001 [chi-square test]). The mutations fell most commonly in ATM (50%), followed by TP53, BRCA2, EGFR, and PARK2. Most (86%) of these variants had been reported in other familial cancer syndromes. Another 12 cases (2%) carried ultrarare variants that were predicted to be deleterious by three protein prediction programs; these most frequently involved ATM and BRCA2. CONCLUSIONS: A subset of patients with lung adenocarcinoma, at least 2.5% to 4.5%, carry germline variants that have been linked to cancer risk in Mendelian syndromes. The genes fall most frequently in DNA repair pathways. Our data indicate that patients with lung adenocarcinoma, similar to other solid tumors, include a subset of patients with inherited susceptibility.
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Adenocarcinoma/genética , Reparo do DNA/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
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 (93.3%) canonical splice sites of five genes. The combined method, CryptSplice, identified and correctly predicted the effect of 18 of 21 (86%) known splice-altering variants in CFTR, a well-studied gene whose loss-of-function variants cause cystic fibrosis (CF). Among 1,423 unannotated CFTR disease-associated variants, the method identified 32 potential exonic cryptic splice variants, two of which were experimentally evaluated and confirmed. After complete CFTR sequencing, the method found three cryptic intronic splice variants (one known and two experimentally verified) that completed the molecular diagnosis of CF in 6 of 14 individuals. CryptSplice interrogation of sequence data from six individuals with X-linked dyskeratosis congenita caused by an unknown disease-causing variant in DKC1 identified two splice-altering variants that were experimentally verified. To assess the extent to which disease-associated variants might activate cryptic splicing, we selected 458 pathogenic variants and 348 variants of uncertain significance (VUSs) classified as high confidence from ClinVar. Splice-site activation was predicted for 129 (28%) of the pathogenic variants and 75 (22%) of the VUSs. Our findings suggest that cryptic splice-site activation is more common than previously thought and should be routinely considered for all variants within the transcribed regions of genes.
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Proteínas de Ciclo Celular/genética , Biologia Computacional , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Variação Genética , Proteínas Nucleares/genética , Sítios de Splice de RNA , Algoritmos , Proteínas de Ciclo Celular/metabolismo , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Disceratose Congênita/genética , Éxons , Regulação da Expressão Gênica , Loci Gênicos , Genômica , Células HEK293 , Humanos , Íntrons , Mutação de Sentido Incorreto , Proteínas Nucleares/metabolismo , Splicing de RNA , Análise de Sequência de DNA , Máquina de Vetores de SuporteRESUMO
In the past five decades, alpha-1 antitrypsin deficiency has been the only known genetic cause of emphysema, yet it explains the genetics in only 1-2% of severe cases. Recently, mutations in telomerase genes were found to induce susceptibility to young-onset, severe, and familial emphysema at a frequency comparable to that of alpha-1 antitrypsin deficiency. Telomerase mutation carriers with emphysema report a family history of idiopathic pulmonary fibrosis, and both lung phenotypes show autosomal dominant inheritance within families. The data so far point to a strong gene-environment interaction that determines the lung disease type. In never-smokers, pulmonary fibrosis predominates, while smokers, especially females, are at risk for developing emphysema alone or in combination with pulmonary fibrosis. The telomere-mediated emphysema phenotype appears to have clinically recognizable features that are distinct from alpha-1 antitrypsin deficiency, and patients are prone to developing short telomere syndrome comorbidities that influence clinical outcomes. In animal models, telomere dysfunction causes alveolar epithelial stem cell senescence, which is sufficient to drive lung remodeling and recruit inflammation. Here, we review the implications of these discoveries for understanding emphysema biology as well as for patient care.
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Fibrose Pulmonar Idiopática/genética , Enfisema Pulmonar/genética , Fumar/epidemiologia , Telomerase/genética , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Fibrose Pulmonar Idiopática/epidemiologia , Enfisema Pulmonar/epidemiologia , Fatores Sexuais , Fumar Tabaco , Deficiência de alfa 1-Antitripsina/genéticaRESUMO
Chronic obstructive pulmonary disease and pulmonary fibrosis have been hypothesized to represent premature aging phenotypes. At times, they cluster in families, but the genetic basis is not understood. We identified rare, frameshift mutations in the gene for nuclear assembly factor 1, NAF1, a box H/ACA RNA biogenesis factor, in pulmonary fibrosis-emphysema patients. The mutations segregated with short telomere length, low telomerase RNA levels, and extrapulmonary manifestations including myelodysplastic syndrome and liver disease. A truncated NAF1 was detected in cells derived from patients, and, in cells in which the frameshift mutation was introduced by genome editing, telomerase RNA levels were reduced. The mutant NAF1 lacked a conserved carboxyl-terminal motif, which we show is required for nuclear localization. To understand the disease mechanism, we used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein-9 nuclease) to generate Naf1(+/-) mice and found that they had half the levels of telomerase RNA. Other box H/ACA RNA levels were also decreased, but rRNA pseudouridylation, which is guided by snoRNAs, was intact. Moreover, first-generation Naf1(+/-) mice showed no evidence of ribosomal pathology. Our data indicate that disease in NAF1 mutation carriers is telomere-mediated; they show that NAF1 haploinsufficiency selectively disturbs telomere length homeostasis by decreasing the levels of telomerase RNA while sparing rRNA pseudouridylation.
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Enfisema/genética , Fibrose Pulmonar/genética , RNA/genética , Animais , Proteínas Relacionadas à Autofagia , Proteínas de Transporte/genética , Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Immunoblotting , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Proteínas do Tecido Nervoso/genética , Ribonucleoproteínas/genética , Telomerase/genética , Telômero/genéticaRESUMO
C4 photosynthesis is a complex phenotype that allows more efficient carbon capture than the ancestral C3 pathway. In leaves of C4 species, hundreds of transcripts increase in abundance compared with C3 relatives and become restricted to mesophyll (M) or bundle sheath (BS) cells. However, no mechanism has been reported that regulates the compartmentation of multiple enzymes in M or BS cells. We examined mechanisms regulating CARBONIC ANHYDRASE4 (CA4) in C4 Gynandropsis gynandra. Increased abundance is directed by both the promoter region and introns of the G. gynandra gene. A nine-nucleotide motif located in the 5' untranslated region (UTR) is required for preferential accumulation of GUS in M cells. This element is present and functional in three additional 5' UTRs and six 3' UTRs where it determines accumulation of two isoforms of CA and pyruvate,orthophosphate dikinase in M cells. Although the GgCA4 5' UTR is sufficient to direct GUS accumulation in M cells, transcripts encoding GUS are abundant in both M and BS. Mutating the GgCA4 5' UTR abolishes enrichment of protein in M cells without affecting transcript abundance. The work identifies a mechanism that directs cell-preferential accumulation of multiple enzymes required for C4 photosynthesis.
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Cleome/genética , Proteínas de Plantas/metabolismo , Anidrases Carbônicas/genética , Anidrases Carbônicas/metabolismo , Cleome/citologia , Cleome/enzimologia , Genes Reporter , Íntrons/genética , Células do Mesofilo/enzimologia , Fotossíntese/genética , Folhas de Planta/citologia , Folhas de Planta/enzimologia , Folhas de Planta/genética , Proteínas de Plantas/genética , Regiões Promotoras Genéticas/genética , Alinhamento de Sequência , Regiões não Traduzidas/genéticaAssuntos
Neoplasias da Mama/radioterapia , Carcinoma Ductal de Mama/radioterapia , Mutação em Linhagem Germinativa , Lesões por Radiação/genética , Tolerância a Radiação/genética , Encurtamento do Telômero/genética , Sobrevivência Celular , Feminino , Humanos , Pessoa de Meia-Idade , Necrose/genética , Lesões por Radiação/patologia , Radioterapia Adjuvante , Fraturas das Costelas/etiologia , Síndrome , Parede Torácica/patologia , Parede Torácica/cirurgia , Cicatrização/genéticaRESUMO
Recent advances have defined a role for abnormally short telomeres in a broad spectrum of genetic disorders. They include rare conditions such as dyskeratosis congenita as well pulmonary fibrosis and emphysema. Now, there is new evidence that some familial cancers, such as melanoma, are caused by mutations that lengthen telomeres. Here, we examine the significance of these short and long telomere length extremes for understanding the molecular basis of age-related disease and cancer.
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Envelhecimento/genética , Neoplasias/genética , Telômero/genética , Envelhecimento/patologia , Humanos , Medicina Molecular , Mutação , Neoplasias/patologia , Telomerase/genética , Homeostase do Telômero/genética , Encurtamento do Telômero/genéticaRESUMO
BACKGROUND: Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease. METHODS: Clinical and pathologic data were reviewed as part of a Johns Hopkins-based natural history study of short telomere syndromes including dyskeratosis congenita. RESULTS: Hepatopulmonary syndrome (HPS) was diagnosed in nine of 42 cases (21%). Their age at presentation was significantly younger than that of cases initially presenting with pulmonary fibrosis and emphysema (median, 25 years vs 55 years; P < .001). Cases had evidence of intra- and extrapulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplantation was 6 years (range, 4-10 years; n = 6). In cases that underwent liver transplantation, dyspnea and hypoxia improved, but pulmonary fibrosis subsequently developed. CONCLUSIONS: This report identifies HPS as a frequent cause of dyspnea in telomerase and telomere gene mutation carriers. While it usually precedes the development of parenchymal lung disease, HPS may also co-occur with pulmonary fibrosis and emphysema. Recognizing this genetic diagnosis is critical for management, especially in the lung and liver transplantation setting.
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Dispneia/etiologia , Síndrome Hepatopulmonar/genética , Mutação , Homeostase do Telômero , Telômero/genética , Adolescente , Adulto , Idoso , Dispneia/genética , Dispneia/metabolismo , Feminino , Síndrome Hepatopulmonar/complicações , Síndrome Hepatopulmonar/metabolismo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Telomerase/genéticaRESUMO
Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.
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Alvéolos Pulmonares/patologia , Células-Tronco/patologia , Encurtamento do Telômero , Telômero/patologia , Envelhecimento/patologia , Animais , Diferenciação Celular , Proliferação de Células , Células Epiteliais/metabolismo , Deleção de Genes , Imunidade , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular , Mesoderma/patologia , Camundongos , Comunicação Parácrina , Peptídeos/metabolismo , Alvéolos Pulmonares/metabolismo , Proteína C Associada a Surfactante Pulmonar , Transdução de Sinais/imunologia , Esferoides Celulares/patologia , Células Estromais/patologia , Proteína 2 de Ligação a Repetições Teloméricas/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
During pancreas development, endocrine precursors and their progeny differentiate, migrate, and cluster to form nascent islets. The transcription factor Neurogenin 3 (Neurog3) is required for islet development in mice, but its role in these dynamic morphogenetic steps has been inferred from fixed tissues. Moreover, little is known about the molecular genetic functions of NEUROG3 in human islet development. We developed methods for gene transduction by viral microinjection in the epithelium of cultured Neurog3-null mutant fetal pancreas, permitting genetic complementation in a developmentally relevant context. In addition, we developed methods for quantitative assessment of live-cell phenotypes in single developing islet cells. Delivery of wild-type NEUROG3 rescued islet differentiation, morphogenesis, and live cell deformation, whereas the patient-derived NEUROG3(R107S) allele partially restored indicators of islet development. NEUROG3(P39X), a previously unreported patient allele, failed to restore islet differentiation or morphogenesis and was indistinguishable from negative controls, suggesting that it is a null mutation. Our systems also permitted genetic suppression analysis and revealed that targets of NEUROG3, including NEUROD1 and RFX6, can partially restore islet development in Neurog3-null mutant mouse pancreata. Thus, advances described here permitted unprecedented assessment of gene functions in regulating crucial dynamic aspects of islet development in the fetal pancreas.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Regulação da Expressão Gênica no Desenvolvimento , Ilhotas Pancreáticas/embriologia , Proteínas do Tecido Nervoso/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Mutations in the essential telomerase genes TERT and TR cause familial pulmonary fibrosis; however, in telomerase-null mice, short telomeres predispose to emphysema after chronic cigarette smoke exposure. Here, we tested whether telomerase mutations are a risk factor for human emphysema by examining their frequency in smokers with chronic obstructive pulmonary disease (COPD). Across two independent cohorts, we found 3 of 292 severe COPD cases carried deleterious mutations in TERT (1%). This prevalence is comparable to the frequency of alpha-1 antitrypsin deficiency documented in this population. The TERT mutations compromised telomerase catalytic activity, and mutation carriers had short telomeres. Telomerase mutation carriers with emphysema were predominantly female and had an increased incidence of pneumothorax. In families, emphysema showed an autosomal dominant inheritance pattern, along with pulmonary fibrosis and other telomere syndrome features, but manifested only in smokers. Our findings identify germline mutations in telomerase as a Mendelian risk factor for COPD susceptibility that clusters in autosomal dominant families with telomere-mediated disease including pulmonary fibrosis.
Assuntos
Transtornos Cromossômicos , Enfisema Pulmonar , Sistema de Registros , Caracteres Sexuais , Fumar , Telomerase , Adulto , Animais , Transtornos Cromossômicos/enzimologia , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Feminino , Humanos , Incidência , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Pneumotórax/enzimologia , Pneumotórax/epidemiologia , Pneumotórax/genética , Pneumotórax/patologia , Prevalência , Enfisema Pulmonar/enzimologia , Enfisema Pulmonar/epidemiologia , Enfisema Pulmonar/genética , Enfisema Pulmonar/patologia , Fibrose Pulmonar/enzimologia , Fibrose Pulmonar/epidemiologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Fatores Sexuais , Fumar/epidemiologia , Fumar/genética , Fumar/metabolismo , Fumar/patologia , Telomerase/genética , Telomerase/metabolismo , Telômero/enzimologia , Telômero/genética , Telômero/patologia , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismoRESUMO
BACKGROUND: Short telomeres are a common defect in idiopathic pulmonary fibrosis, yet mutations in the telomerase genes account for only a subset of these cases. METHODS: We identified a family with pulmonary fibrosis, idiopathic infertility, and short telomeres. RESULTS: Exome sequencing of blood-derived DNA revealed two mutations in the telomere-binding protein TINF2. The first was a 15-base-pair deletion encompassing the exon 6 splice acceptor site, and the second was a missense mutation, Thr284Arg. Haplotype analysis indicated both variants fell on the same allele. However, lung-derived DNA showed predominantly the Thr284Arg allele, indicating that the deletion seen in the blood was acquired and may have a protective advantage because it diminished expression of the missense mutation. This mosaicism may represent functional reversion in telomere syndromes similar to that described for Fanconi anemia. No mutations were identified in over 40 uncharacterized pulmonary fibrosis probands suggesting that mutant TINF2 accounts for a small subset of familial cases. However, similar to affected individuals in this family, we identified a history of male and female infertility preceding the onset of pulmonary fibrosis in 11% of TERT and TR mutation carriers (five of 45). CONCLUSIONS: Our findings identify TINF2 as a mutant telomere gene in familial pulmonary fibrosis and suggest that infertility may precede the presentation of pulmonary fibrosis in a small subset of adults with telomere syndromes.