RESUMO
We report an example of atypical CF, i.e., a family in which three siblings were affected by late-diagnosed mild CF, and showed discordant pulmonary and pancreatic phenotypes. Sibling no. 1 (male), showed a severe pulmonary involvement and pancreatic sufficiency; sibling no. 2 (female) showed a mild pulmonary disease with pancreatic sufficiency; sibling no. 3 (male) had a very mild pulmonary expression and pancreatic insufficiency. The sweat test was altered in all three siblings, and all had intestinal occlusion in young age. The whole scanning of CFTR revealed the rare F508del/D614G genotype. The discordance of clinical expression within the same family reinforces the putative role of modifier genes of CF phenotype.
Assuntos
Bronquiectasia/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Insuficiência Pancreática Exócrina/genética , Ducto Deferente/patologia , Idade de Início , Fibrose Cística/complicações , Fibrose Cística/patologia , Genótipo , Humanos , Obstrução Intestinal/etiologia , Obstrução Intestinal/genética , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , IrmãosRESUMO
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been shown to cause typical cystic fibrosis (CF) and several milder phenotypes. We report on two asymptomatic sisters who had isolated increased sweat chloride concentrations, and in whom systematic scanning of the whole coding region of the CFTR gene revealed the F508del/S1455X genotype.
Assuntos
Cloretos/metabolismo , Códon sem Sentido , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Suor/química , Adulto , Criança , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , MutaçãoRESUMO
We report on a 10-month-old boy with hypotonic dehydration and metabolic alkalosis. Sweat test was borderline and genetic analysis was negative for common mutations. Analysis of the whole coding regions of the CFTR gene revealed the rare mutation D579G in homozygosity.
Assuntos
Alcalose/diagnóstico , Alcalose/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Mutação de Sentido Incorreto , Alcalose/etiologia , Fibrose Cística/complicações , Homozigoto , Humanos , Lactente , MasculinoRESUMO
Mucopolysaccharidosis type IIIB (MPS IIIB; or Sanfilippo syndrome type B) is a lysosomal disease, due to glycosaminoglycan storage caused by mutations on the alpha-N-acetylglucosaminidase (NAGLU) gene. The disease is characterized by neurological dysfunction but relatively mild somatic manifestations. No effective treatment is available for affected patients. In the present study, we evaluated the role of a lentiviral vector as the transducing agent of NAGLU cDNA in MPS IIIB fibroblasts. The vector expressed high transduction efficiency and high levels of enzymic activity, 20-fold above normal levels, persisting for at least 2 months. PCR experiments confirmed the integration of the viral vector into the target genome. The NAGLU activity restored by virus infection was sufficient to normalize glycosaminoglycan accumulation, which is directly responsible for the disease phenotype. Metabolic labelling experiments on transduced fibroblasts exhibited, in the medium and in cellular lysates, polypeptide forms of 84 and 80 kDa respectively related to the precursor and mature forms of the enzyme. The enzyme secreted by transduced MPS IIIB fibroblasts was endocytosed in deficient cells by the mannose 6-phosphate system. Thus we show that lentiviral vectors may provide a therapeutic approach for the treatment of MPS IIIB disease.
