Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.660
Filtrar
1.
N Engl J Med ; 381(19): 1809-1819, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697873

RESUMO

BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4. RESULTS: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).


Assuntos
Aminofenóis/administração & dosagem , Benzodioxóis/administração & dosagem , Agonistas dos Canais de Cloreto/administração & dosagem , Fibrose Cística/tratamento farmacológico , Indóis/administração & dosagem , Mutação , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Quinolonas/administração & dosagem , Adolescente , Adulto , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Criança , Agonistas dos Canais de Cloreto/efeitos adversos , Cloretos/análise , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Genótipo , Humanos , Indóis/efeitos adversos , Masculino , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Quinolonas/efeitos adversos , Suor/química , Adulto Jovem
2.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(3): 420-424, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31631611

RESUMO

Objective: To investigate the expression of cystic fibrosis transmembrane conductance regulator (CFTR) protein in patients with acute leukemia and its relationship to clinical features and prognosis of acute leukemia. Methods: A total of115 patients with acute leukemia were enrolled in the experimental group and 20 healthy individuals were used as control. Peripheral blood or bone marrow samples were collected, and mononuclear cells were isolated. The expression of CFTR protein was detected by Western blot. The relationships of CFTR protein expression to clinical features and prognosis was analyzed. Results: The expression of CFTR protein was not detected in peripheral blood mononuclear cells of normal control, while it was positive in more than half of acute leukemias including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), but negative in the patients with acute promyelocytic leukemia (M3). In the patients with AML, there was no difference in peripheral white blood cells (WBC), peripheral blast cells, platelet and hemoglobin (HGB) between CFTR-positive and CFTR-negative patients. There was no relationship between the expression of CFTR protein and gene mutations such as NPM1, CEBPA, FLT3-ITD, and C-Kit. Complete remission (CR) rate after two course in CFTR-negative patients was slightly higher than that in positive patients. The survival time of CFTR-negative patients was little longer than that of positive patients, but the difference was not statistically significant. Conclusions: The expression of CFTR protein seems not associated with clinical features, treatment response and prognosis in the patients with acute leukemia.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Leucemia Mieloide Aguda/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucócitos Mononucleares , Mutação , Prognóstico
4.
Cell Physiol Biochem ; 53(2): 400-412, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31403270

RESUMO

BACKGROUND/AIMS: Mutations in ABCA4 cause Stargardt macular degeneration, which invariably ends in legal blindness. We studied two common mutants, A1038V (in NBD1) and G1961E (in NBD2), with the purpose of exploring how they interact with the cell's quality control mechanism. The study was designed to determine how these mutants can be rescued. METHODS: We expressed wt and mutant ABCA4 in HEK293 cells and studied the effect of the mutations on trafficking and processing and the ability of correctors to rescue them. We used a combination of western blotting, confocal microscopy and surface biotinylation coupled with pulldown of plasma membrane proteins. RESULTS: G1961E is sensitive to inhibitors of the aggresome, tubacin and the lysosome, bafilomycin A. Both mutants cause a reduction in heat shock protein, Hsp27. Incubation of HEK293 cells expressing the mutants with VX-809, an FDA approved drug for the treatment of cystic fibrosis, increased the levels of A1038V and G1961E by 2- to 3-fold. Importantly, VX-809 increased the levels of both mutants at the plasma membrane suggesting that trafficking had been restored. Transfecting additional Hsp27 to the cells also increased the steady state levels of both mutants. However, in combination with VX-809 the addition of Hsp27 caused a dramatic increase in the protein expression particularly in the G1961 mutant which increased approximately 5-fold. CONCLUSION: Our results provide a new mechanism for the rescue of ABCA4 trafficking mutants based on the restoration of Hsp27. Our results provide a pathway for the treatment of Stargardt disease.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Transportadores de Cassetes de Ligação de ATP/genética , Aminopiridinas/uso terapêutico , Anilidas/farmacologia , Benzodioxóis/uso terapêutico , Membrana Celular/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Leupeptinas/farmacologia , Lisossomos/metabolismo , Degeneração Macular/congênito , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Mutação , Transporte Proteico/efeitos dos fármacos
5.
Urologiia ; (3): 101-107, 2019 Jul.
Artigo em Russo | MEDLINE | ID: mdl-31356021

RESUMO

AIM: microdeletions in the AZF region of Y-chromosome, compound heterozygotes of severe and mild CFTR mutations, and long CAG-repeats in the androgen receptor gene (AR) as marker of predisposition are frequently studied as genetic causes of male infertility. A simultaneously testing of the panel including biochemical, immunological, cyto- and molecular genetic markers is often performed during the complex laboratory diagnostics in infertile men. The aim of our work was to identify molecular genetic alterations, which are advisable for simultaneously testing in a man with currently uncertain form of infertility, to increase the informativeness of laboratory diagnostics. MATERIALS AND METHODS: a retrospective study of 885 infertile men was conducted. AZF deletions were determined by multiplex PCR using 10 STS-markers (sY83, sY84, sY86, sY127, sY134, sY143, sY152, sY157, sY254, sY255) and two control loci SRY and AMEL with detection in polyacrylamide gel. Mutations in the CFTR gene (F508del, CFTRdel2.3(21kb), I507del, 1677delTA, 2143delT, 2184insA, 394delTT, W1282X, G542X, N1303K, R334W and 5T) were detected by PCR and SNaPshot. For determination of length of the AR CAG-repeat a fragment analysis of fluorescently labeled PCR products on the 3500xl capillary sequencer was performed. RESULTS: AZF deletions were detected in 8.2% of cases. The largest number of deletions was found in the AZFc subregion (58.9%), while a frequency of deletion in AZFa, AZFb or combined deletions of two and three subregions was 5.5%, 12.3% and 23.3%, respectively. Heterozygous carriage of severe CFTR mutations was detected in 4.7% patients. The most frequent mutation was F508del (83.3%), followed by CFTRdel21kb (7.1%) and W1282X (4.8%). The frequency of the mild splicing 5T mutation was 5.3%, and its incidence was significantly higher than in the previously published control group (p=0.002). AR genotyping revealed that the most prevailing allele was 21 (CAG) (21.5%). Long alleles with 27 or more CAG-trinucleotides were identified in 7.5% of the tested cases. In addition, 7 CAG heterozygotes with Kleinfelter syndrome were found. CONCLUSION: during primary complex laboratory diagnostics in a heterogeneous group of infertile men, it is advisable to detect AZF deletions and the most frequent CFTR mutations, including F508del, CFTRdel21kb, 1677delTA, 2143delT, W1282X and 5T. The more comprehensive analysis of CFTR mutations is justified only in patients with verified obstructive infertility. Sequencing of panels associated with infertility genes using NGS technology is promising.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Infertilidade Masculina , Oligospermia , Alelos , Biomarcadores , Cromossomos Humanos Y , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Incidência , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/genética , Masculino , Mutação , Estudos Retrospectivos
6.
Gene ; 719: 144007, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31357024

RESUMO

Congenital bilateral absence of vas deferens (CBAVD), a frequent cause of obstructive azoospermia and male infertility in Chinese, is mainly due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This study aim to explore the promoter region of CFTR gene in CBAVD patients and study the mutations by functional analysis, and to discuss the significance of mutation testing in this area. We performed screening analysis on 65 CBAVD patients and 50 controls to detect mutations in the CFTR gene, and studied the functions of promoter mutations using reporter gene constructs, transient transfection techniques and subsequent assessment of transcriptional activity and expression levels. Mutations c.-195C>A and c.-34C>T in the promoter region of the CFTR gene were detected in 4 of our Chinese CBAVD patients, one of which was novel (c.-195C>A) and located in the conservative area, as well as the binding site of SP1 transcription factor through the prediction of bioinformatics analysis. By reverse transcription qPCR assay and luciferase assay, we validated it as a functional disease-causing variant that down-regulates the CFTR gene expression, and this effect was related to the amount of transcription factors. This study was the first to explore the promoter region of the CFTR gene in Chinese, and we believe that mutations in this region are associated with Chinese CBAVD patients. We also suggest a systematic strategy for genotyping Chinese CBAVD couples, which should help in developing reproductive counseling.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Doenças Urogenitais Masculinas/genética , Mutação , Regiões Promotoras Genéticas , Ducto Deferente/anormalidades , Adulto , Linhagem Celular , China , Regulação para Baixo , Genes Reguladores , Aconselhamento Genético , Humanos , Masculino , Reprodução , Adulto Jovem
7.
Nat Commun ; 10(1): 2636, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201318

RESUMO

The leading cause of cystic fibrosis (CF) is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). The mutation affects the thermodynamic stability of the domain and the integrity of the interface between NBD1 and the transmembrane domain leading to its clearance by the quality control system. Here, we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein. Crystal structures of NBD1-nanobody complexes provide an atomic description of the epitopes and reveal the molecular basis for stabilization. Furthermore, our data uncover a conformation of CFTR, involving detachment of NBD1 from the transmembrane domain, which contrast with the compact assembly observed in cryo-EM structures. This unexpected interface rearrangement is likely to have major relevance for CF pathogenesis but also for the normal function of CFTR and other ABC proteins.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Modelos Moleculares , Cristalografia por Raios X , Regulador de Condutância Transmembrana em Fibrose Cística/isolamento & purificação , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas/genética , Estabilidade Proteica , Estrutura Terciária de Proteína/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Deleção de Sequência , Anticorpos de Domínio Único/metabolismo
8.
Croat Med J ; 60(3): 246-249, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31187952

RESUMO

The diagnosis of cystic fibrosis (CF) is commonly confirmed by molecular genetics with the presence of specific mutations of cystic fibrosis transmembrane conductance regulator (CFTR) gene. We report a case of cystic fibrosis (CF) in a 15-year-old female patient who is a compound heterozygote for CFTR gene, with delta F508 and Tyr109Glyfs mutations detected. This is the first detailed description of such a case in the medical literature. The primary CF presentation occurred at the age of 9 in the form of gastrointestinal symptoms including greasy, bulky, and foul-smelling stool. The patient exhibited delayed growth, with her height and weight being below the 5th centile for age according to the World Health Organization growth curves. Pancreatic enzyme supplement treatment was started immediately, alongside high-fat and high-calorie diet, resulting in patient's recovery and development. DNA analysis of CFTR gene demonstrated the presence of del. F508 mutation and a rare combining deletion and insertion mutation p. Tyr109Glyfs. The combination of the two mutations is very rare in CF patients and is therefore valuable to document this case in order to provide information on disease progression, therapy options, and outcomes. With standard treatment and early diagnosis, the patient is currently doing well and is not restricted by the disease in her daily and sports activities.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Fibrose Cística/terapia , Adolescente , Criança , Fibrose Cística/diagnóstico , Feminino , Heterozigoto , Humanos , Mutação INDEL
9.
BMC Med Genet ; 20(1): 89, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126253

RESUMO

BACKGROUND: Cystic fibrosis has been largely under-diagnosed and thus, limited data is available on the incidence of cystic fibrosis in Sri Lanka. Our aim is to describe the phenotypic and genotypic spectrum of children with cystic fibrosis in Sri Lanka. CASE PRESENTATION: This report describes 10 unrelated cystic fibrosis cases with phenotypic features of cystic fibrosis and abnormal or intermediate sweat tests. The most common phenotypic features in this sample of symptomatic patients were persistent or recurrent lower respiratory tract infections, failure to thrive and Pseudo-Bartter syndrome. Altogether 7 cystic fibrosis causing mutations were identified in 10 patients. Except delta F508 which is the commonest mutation worldwide all the other mutations detected in Sri Lankan patients are rare mutations. 1161delC and V456A detected in our patients are South Asian mutations. The other mutations such as [C.1282C > G; C.2738A > G], C.53 + 1G > C, 2184insA and a deletion encompassing exons 4 to 11 have been reported previously from European patients with cystic fibrosis. CONCLUSION: These cases highlight the importance of considering the diagnosis of cystic fibrosis in children and young adults presenting with persistent respiratory tract infections associated with severe malnutrition and Pseudo-Bartter syndrome, especially in low income countries where newborn screening for cystic fibrosis is not available. The spectrum of CFTR mutations in Sri Lanka is heterogeneous and possibly linked to genetic flow from Indian subcontinent and Europe. The common mutations should be identified by sequencing the entire CFTR gene in adequate number of cystic fibrosis patients in order to design a mutation panel for common regional mutations.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Heterogeneidade Genética , Mutação , Criança , Pré-Escolar , Fibrose Cística/patologia , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente , Masculino , Fenótipo , Sri Lanka , Adulto Jovem
11.
Nat Commun ; 10(1): 1763, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992452

RESUMO

Personalized approaches for systematically assessing ciliary beat dynamics and for drug testing would improve the challenging task of diagnosing and treating respiratory disorders. In this pilot study, we show how multiscale differential dynamic microscopy (multi-DDM) can be used to characterize collective ciliary beating in a non-biased automated manner. We use multi-DDM to assess the efficacy of different CFTR-modulating drugs in human airway epithelial cells derived from subjects with cystic fibrosis (ΔF508/ΔF508 and ∆F508/-) based on ciliary beat frequency and coordination. Similar to clinical observations, drug efficacy is variable across donors, even within the same genotype. We show how our assay can quantitatively identify the most efficient drugs for restoring ciliary beating for each individual donor. Multi-DDM provides insight into ciliary beating responses following treatment with drugs, and has application in the broader context of respiratory disease and for drug screening.


Assuntos
Brônquios/metabolismo , Cílios/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/metabolismo , Algoritmos , Aminofenóis/química , Aminopiridinas/química , Benzodioxóis/química , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Progressão da Doença , Células Epiteliais/metabolismo , Genótipo , Humanos , Microscopia , Oscilometria , Fenótipo , Quinolonas/química , Gravação em Vídeo
12.
BMC Pulm Med ; 19(1): 76, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975115

RESUMO

BACKGROUND: CFTR modulator therapy with ivacaftor is a treatment option for Cystic Fibrosis (CF) patients with at least one copy of a R117H-7T mutation in the CFTR gene. Desirable effects of this therapy are improvement of lung function, decrease in exacerbation rate, normalization or reduction of sweat chloride and weight gain. Monogenetic CF-twins carry identical genetic information, so therapy response and side effects are expected to be nearly identical under this specific therapy. CASE PRESENTATION: In monozygotic twins, at the age of 55, two pathogenic variants in the CFTR gene (F508del and R117H-7T) were detected. Both patients presented with a borderline sweat test (30-59 mmol/L) and despite the same genetic information and similar life circumstances the disease proceeds completely different. While one patient has severe pulmonary involvement with chronic P. aeruginosa infection, her twin sister is almost unimpaired. Liver or pancreatic involvement was not seen in either patient. Due to the presence of one copy of a R117H-7T mutation, CFTR modulator therapy with ivacaftor was initiated in both. Response and side effects were significantly different. In the less affected patient, we observed an improvement in lung function and a normalization of sweat chloride. In the severely affected patient, no functional response to treatment was seen, but stabilization of the disease state with a decrease in exacerbation and hospitalization rate and weight gain as well as a normalization of sweat chloride. There was an increase in liver enzymes in the less affected patient, which normalized after halving the dose of ivacaftor, while the therapeutic effect was maintained. CONCLUSIONS: Despite nearly identical genetic information, as in monogenetic twins, therapy response and onset of side effects of CFTR modulating therapy are very different. In patients with late diagnosis and severe pulmonary involvement, ivacaftor does not seem to improve lung function, whereas in patients with late diagnosis and low disease severity a relevant therapy response was obtained. In addition to lung function, additional clinical parameters such as reduction of exacerbation and hospitalization rate and weight gain should be used to assess therapy response, especially in severely affected patients.


Assuntos
Aminofenóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Quinolonas/uso terapêutico , Gêmeos Monozigóticos/genética , Fibrose Cística/genética , Feminino , Volume Expiratório Forçado , Heterozigoto , Humanos , Pulmão/fisiopatologia , Pessoa de Meia-Idade , Mutação
13.
Cell Physiol Biochem ; 52(6): 1267-1279, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31026390

RESUMO

BACKGROUND/AIMS: Because of the small size of adeno-associated virus, AAV, the cystic fibrosis conductance regulator, CFTR, cDNA is too large to fit within AAV and must be truncated. We report here on two truncated versions of CFTR, which, when inserted into AAV1 and used to infect airway cells, rescue F508-del CFTR via transcomplementation. The purpose of this study is to shed light on where in the cell transcomplementation occurs and how it results in close association between the endogenous F508-del and truncated CFTR. METHODS: We treated CF airway cells (CFBE41o-) with AAV2/1 (AAV2 inverted terminal repeats/AAV1 capsid) containing truncated forms of CFTR, ∆264 and ∆27-264 CFTR, who can restore the function of F508-del by transcomplementation. We addressed the aims of the study using a combination of confocal microscopy and short circuit currents measurements. For the latter, CF bronchial epithelial cells (CFBE) were grown on permeable supports. RESULTS: We show that both F508del and the truncation mutants colocalize in the ER and that both the rescued F508-del and the transcomplementing mutants reach the plasma membrane together. There was significant fluorescence resonance energy transfer (FRET) between F508-del and the transcomplementing mutants within the endoplasmic reticulum (ER), suggesting that transcomplementation occurs through a bimolecular interaction. We found that transcomplementation could increase the Isc in CFBE41o- cells stably expressing additional wt-CFTR or F508-del and in parental CFBE41o- cells expressing endogenous levels of F508-del. CONCLUSION: We conclude that the functional rescue of F508-del by transcomplementation occurs via a bimolecular interaction that most likely begins in the ER and continues at the plasma membrane. These results come at an opportune time for developing a gene therapy for CF and offer new treatment options for a wide range of CF patients.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Dependovirus/genética , Retículo Endoplasmático/genética , Linhagem Celular , Fibrose Cística/terapia , Terapia Genética , Humanos , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Deleção de Sequência , Transfecção
14.
Pediatr Ann ; 48(4): e154-e161, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30986316

RESUMO

Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection. This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF. Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. Diagnosis of CF is confirmed by demonstration of elevated sweat chloride. Most cases of CF are identified through newborn screening (NBS). There are also infants with positive NBS but inconclusive diagnostic testing; a small proportion of these infants may go on to develop CF. CF is a lifelong, life-limiting disease, but an organized care center network with multidisciplinary approach, quality improvement initiatives, and research has led to markedly increased survival and development of adult CF care programs. In the past few years, medications that directly target the underlying CF defect have been developed, which should result in even greater survival benefits. [Pediatr Ann. 2019;48(4):e154-e161.].


Assuntos
Fibrose Cística/diagnóstico , Triagem Neonatal/métodos , Fibrose Cística/complicações , Fibrose Cística/terapia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Lactente , Recém-Nascido , Mutação
15.
Transplant Proc ; 51(3): 790-793, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30979466

RESUMO

Cystic fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene, deranging the activity of chloride channels on the epithelial cell surface. Herein we describe end-stage liver disease in 3 infants with rare CFTR gene mutations; 2 of them were heterozygous. Case 1 was a premature male infant with negative CF screening at birth who developed a small bowel obstruction in the neonatal period requiring an ileostomy, with subsequent cholestatic liver disease and portal hypertension. In addition, he was noted to have frequent respiratory infections prompting a sweat test, which was positive. Genetic testing revealed that he was heterozygous for P.1177F. He then underwent a successful liver transplant. Case 2 was a female infant who developed progressive cholestasis with poor weight gain and was found to have neonatal hepatitis on liver biopsy. A sweat test was negative and genetic testing revealed she was heterozygous for CFTR and PEX26 gene mutations. She subsequently developed pneumatosis involving the cecum that was treated conservatively, followed by a successful liver transplant. Case 3 was a male infant who developed progressive liver disease, with liver biopsy showing neonatal hepatitis. He was extensively investigated but had a negative sweat test on repeated studies. Genetic testing revealed that the patient was heterozygous P.K186N-variant in the AKRID1 gene and homozygous P.R75Q-variant in the CFTR gene. Unfortunately, he succumbed to an acute upper gastrointestinal hemorrhage. Rare and unusual CFTR mutations, even in the heterozygous form, may be a feature in otherwise undiagnosed end-stage liver disease of infancy.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Fibrose Cística/patologia , Hepatopatias/genética , Hepatopatias/patologia , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Mutação
16.
Allergol. immunopatol ; 47(2): 159-165, mar.-abr. 2019. tab
Artigo em Inglês | IBECS | ID: ibc-180804

RESUMO

Introduction and Objectives: Asthma is a complex genetic disorder. Several genes have been found associated with asthma. The cystic fibrosis transmembrane conductance regulator (CFTR) gene is one of them. The aim of this study was to perform a comparative analysis of the genotype and allele frequency distributions of the biallelic marker M470V within the CFTR gene on mutant and wide chromosomes. Patients and methods: The molecular approach consists in the genotyping of the M470V marker by the PCR-RFLP technique in 105 asthmatic patients, aged between four months and 17 years, and 105 healthy subjects. Results: We found a significant difference in the genotype frequencies between the two studied groups (chi2 = 9.855, P = 0.007). The V/V genotype was over represented in the asthmatic group as compared to the controls (32.38% vs. 16.19%). Whereas, the M/V genotype is more frequent in healthy subjects (40.95% vs. 28.71%). We also noted a significant difference in allelic distribution of M470V with associated diseases (chi2 = 9.610, P = 0.022). Conclusions: The present study is the first report on the distribution of the M470V polymorphism in asthmatic Tunisian patients. We noticed that the M470V variant could modulate the clinical phenotype of asthmatic patients. This preliminary study will establish the molecular basis of this disease in Tunisia


No disponible


Assuntos
Humanos , Masculino , Lactente , Pré-Escolar , Criança , Adolescente , Asma/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Genótipo , Mutação/genética , Frequência do Gene , Estudos de Associação Genética , Fenótipo
17.
J Bras Pneumol ; 45(1): e20170280, 2019 Feb 28.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30843951

RESUMO

OBJECTIVE: Bone disease is a common comorbidity in patients with cystic fibrosis (CF). We sought to determine risk factors and identify potential biochemical markers for CF-related bone disease (CFBD) in a unique cohort of CF patients with end-stage lung disease undergoing lung transplantation (LTx) evaluation. METHODS: All of the CF patients who were evaluated for LTx at our center between November of 1992 and December of 2010 were included in the study. Clinical data and biochemical markers of bone turnover, as well as bone mineral density (BMD) at the lumbar spine and femoral neck, were evaluated. Spearman's rho and multivariate logistic regression analysis were used. RESULTS: A total of 102 adult CF patients were evaluated. The mean age was 28.1 years (95% CI: 26.7-29.5), and the mean body mass index was 17.5 kg/m2 (95% CI: 17.2-18.2). Mean T-scores were -2.3 and -1.9 at the lumbar spine and femoral neck, respectively, being lower in males than in females (-2.7 vs. -2.0 at the lumbar spine and -2.2 vs. -1.7 at the femoral neck). Overall, 52% had a T-score of < -2.5 at either skeletal site. The homozygous Phe508del genotype was found in 57% of patients without osteoporosis and in 60% of those with low BMD. Mean T-scores were not particularly low in patients with severe CFTR mutations. Although the BMI correlated with T-scores at the femoral neck and lumbar spine, serum 25-hydroxyvitamin D and parathyroid hormone levels did not. CONCLUSIONS: CFBD is common in CF patients with end-stage lung disease, particularly in males and patients with a low BMI. It appears that CF mutation status does not correlate with CFBD. In addition, it appears that low BMD does not correlate with other risk factors or biochemical parameters. The prevalence of CFBD appears to have recently decreased, most likely reflecting increased efforts at earlier diagnosis and treatment.


Assuntos
Fibrose Cística/complicações , Pneumopatias/complicações , Osteoporose/etiologia , Adulto , Índice de Massa Corporal , Densidade Óssea , Remodelação Óssea , Estado Terminal , Fibrose Cística/epidemiologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Modelos Logísticos , Pneumopatias/epidemiologia , Transplante de Pulmão , Masculino , Análise Multivariada , Mutação , Osteoporose/epidemiologia , Hormônio Paratireóideo/sangue , Estudos Retrospectivos , Distribuição por Sexo , Estatísticas não Paramétricas , Suíça/epidemiologia , Vitamina D/análogos & derivados , Vitamina D/sangue
18.
BMC Med Genet ; 20(1): 44, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898088

RESUMO

BACKGROUND: Cystic fibrosis (CF; OMIM #219700) is a common autosomal recessive disease caused by pathogenic variants (henceforward mutations) in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The spectrum and frequencies of CFTR mutations vary among different populations. Characterization of the specific distribution of CFTR mutations can be used to optimize genetic counseling, foster reproductive choices, and facilitate the introduction of mutation-specific therapies. Chechens are a distinct Caucasian ethnic group of the Nakh peoples that originated from the North Caucasus. Chechens are one of the oldest ethnic groups in the Caucasus, the sixth largest ethnic group in the Russian Federation (RF), and constitute the majority population of the Chechen Republic (Chechnya). The spectrum of CFTR mutations in a representative cohort of Chechen CF patients and healthy individuals was analyzed. METHODS: Molecular genetic analysis of 34 CFTR mutations (representing approx. 80-85% of mutations in multiethnic CF populations of the RF) was performed in 32 CF patients from 31 unrelated Chechen families living in Chechnya. One hundred randomly chosen healthy Chechens were analyzed for the 15 most common "Russian" mutations. The clinical symptoms in Chechen CF patients with different CFTR genotypes were investigated. RESULTS: High frequencies of c.1545_1546delTA (p.Tyr515X; 1677delTA) (52 out of 64 CFTR alleles tested; 81.3%) and c.274G > A (p.Glu92Lys, E92K) (8/64, 12.5%) mutations were found. Twenty patients were homozygous for the c.1545_1546delTA mutation, and eight were compound heterozygous for the c.1545_1546delTA and c.274G > A mutations. Three carriers of the c.1545_1546delTA mutation were also found in the cohort of 100 apparently healthy Chechens (frequency - 0.015). The c.1545_1546delTA and c.274G > A mutations are linked to the same haplotype (22-7-16-13) of intragenic Short Tandem Repeat markers, i.e., IVS1CA, IVS6aGATT, IVS8CA, and IVS17bCA. CONCLUSIONS: The distribution of CFTR mutations in the Chechen CF population is unique regarding the high frequency of mutations c.1545_1546delTA and c.274G > A (more than 90% of the mutant alleles). The c.274G > A mutation is associated with a less severe course of CF than that observed in c.1545_1546delTA homozygotes. Testing for these two variants can be proposed as the first step of CF DNA diagnosis in the Chechen population.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Mutação Puntual , Deleção de Sequência , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Fibrose Cística/etnologia , Diagnóstico Precoce , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Federação Russa/etnologia , Índice de Gravidade de Doença
19.
Nature ; 567(7748): 405-408, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867598

RESUMO

Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO3- and Cl- secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis1-3. Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO3- secretion and increased airway surface liquid pH in cultured airway epithelia from people with cystic fibrosis. These effects required the basolateral Na+, K+-ATPase, indicating that apical amphotericin B channels functionally interfaced with this driver of anion secretion. Amphotericin B also restored airway surface liquid pH, viscosity, and antibacterial activity in primary cultures of airway epithelia from people with cystic fibrosis caused by different mutations, including ones that do not yield CFTR, and increased airway surface liquid pH in CFTR-null pigs in vivo. Thus, unselective small-molecule ion channels can restore host defences in cystic fibrosis airway epithelia via a mechanism that is independent of CFTR and is therefore independent of genotype.


Assuntos
Fibrose Cística/metabolismo , Epitélio/metabolismo , Canais Iônicos/metabolismo , Mucosa Respiratória/metabolismo , Sistema Respiratório/metabolismo , Anfotericina B/farmacologia , Animais , Bicarbonatos/metabolismo , Células Cultivadas , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/deficiência , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Epitélio/efeitos dos fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Mucosa Respiratória/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Suínos
20.
Ther Adv Respir Dis ; 13: 1753466618820186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30803355

RESUMO

BACKGROUND: Lumacaftor/ivacaftor combination therapy is efficacious and generally safe for patients with cystic fibrosis (CF) homozygous for the F508del-CF transmembrane conductance regulator (CFTR) mutation. However, long-term survival benefits of lumacaftor/ivacaftor (LUM/IVA) cannot yet be quantified. Simulation models can provide predictions about long-term health outcomes. In this study, we aimed to project long-term health outcomes of LUM/IVA plus standard care (SC) in patients with CF homozygous for F508del-CFTR. METHODS: This modeling study was an individual patient simulation in US patients aged ⩾6 years with CF, homozygous for F508del-CFTR. The primary outcome was projected survival among (a) a cohort of patients who ever initiated LUM/IVA, accounting for treatment discontinuations, and (b) a cohort of patients who remain on continuous LUM/IVA. Patient characteristics and model parameters were derived from clinical trials: VX14-809-109, VX13-809-011B, TRAFFIC/TRANSPORT, and PROGRESS; published literature; and the US CF Foundation Patient Registry. RESULTS: Lumacaftor/ivacaftor + SC is expected to increase median survival by 6.1 years versus SC alone, accounting for treatment discontinuations. The incremental median predicted survival versus SC assuming initiation of LUM/IVA at ages 6, 12, 18, and 25 years was 17.7, 12.6, 8.0, and 3.8 years, respectively. Assuming lifetime treatment with LUM/IVA, incremental median survival was predicted to be 7.8 years longer in the LUM/IVA + SC cohort. Initiating LUM/IVA at ages 6, 12, 18, and 25 years and assuming lifetime treatment resulted in incremental median predicted survival of 23.4, 18.2, 11.0, and 4.8 years, respectively. CONCLUSIONS: Lumacaftor/ivacaftor is projected to increase survival for patients with CF. Initiation at an early age and treatment persistence result in further increments in projected survival.


Assuntos
Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Simulação por Computador , Fibrose Cística/tratamento farmacológico , Modelos Estatísticos , Quinolonas/uso terapêutico , Adolescente , Adulto , Criança , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Feminino , Humanos , Masculino , Mutação , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema de Registros , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA