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1.
Clin Biochem ; 45(4-5): 363-5, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22240068

RESUMO

BACKGROUND: We have investigated whether blood ammonia is increased with worsening CKD. METHODS: Fifty eight subjects with a range of CKD were recruited for analysis of plasma ammonia and other electrolytes. RESULTS: The concentrations of plasma ammonia were all within the normal reference range and there was no correlation between ammonia and CKD without any effect of dialysis. CONCLUSIONS: Blood ammonia is not elevated in or related to the severity of chronic kidney disease.


Assuntos
Amônia/sangue , Rim/fisiopatologia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bicarbonatos/sangue , Creatinina/sangue , Taxa de Filtração Glomerular , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Diálise Renal , Insuficiência Renal Crônica/terapia , Índice de Gravidade de Doença , Ureia/sangue , Uremia/sangue , Uremia/fisiopatologia , Uremia/terapia , Adulto Jovem
2.
Cell Stress Chaperones ; 15(6): 835-49, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20428984

RESUMO

Multiple epiphyseal dysplasia (MED) can result from mutations in matrilin-3, a structural protein of the cartilage extracellular matrix. We have previously shown that in a mouse model of MED the tibia growth plates were normal at birth but developed a progressive dysplasia characterised by the intracellular retention of mutant matrilin-3 and abnormal chondrocyte morphology. By 3 weeks of age, mutant mice displayed a significant decrease in chondrocyte proliferation and dysregulated apoptosis. The aim of this current study was to identify the initial post-natal stages of the disease. We confirmed that the disease phenotype is seen in rib and xiphoid cartilage and, like tibia growth plate cartilage is characterised by the intracellular retention of mutant matrilin-3. Gene expression profiling showed a significant activation of classical unfolded protein response (UPR) genes in mutant chondrocytes at 5 days of age, which was still maintained by 21 days of age. Interestingly, we also noted the upregulation of arginine-rich, mutated in early stage of tumours (ARMET) and cysteine-rich with EGF-like domain protein 2 (CRELD2) are two genes that have only recently been implicated in the UPR. This endoplasmic reticulum (ER) stress and UPR did not lead to increased chondrocyte apoptosis in mutant cartilage by 5 days of age. In an attempt to alleviate ER stress, mutant mice were fed with a chemical chaperone, 4-sodium phenylbutyrate (SPB). SPB at the dosage used had no effect on chaperone expression at 5 days of age but modestly decreased levels of chaperone proteins at 3 weeks. However, this did not lead to increased secretion of mutant matrilin-3 and in the long term did not improve the disease phenotype. We performed similar studies with a mouse model of Schmid metaphyseal chondrodysplasia, but again this treatment did not improve the phenotype.


Assuntos
Proteínas da Matriz Extracelular/genética , Osteocondrodisplasias/metabolismo , Resposta a Proteínas não Dobradas , Animais , Apoptose , Cartilagem/patologia , Cartilagem/ultraestrutura , Condrócitos/metabolismo , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Proteínas Matrilinas , Camundongos , Mutação , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Fenótipo , Fenilbutiratos/farmacologia , Costelas/citologia , Fatores de Tempo , Regulação para Cima
3.
Hum Mol Genet ; 16(14): 1728-41, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17517694

RESUMO

Disruption to endochondral ossification leads to delayed and irregular bone formation and can result in a heterogeneous group of genetic disorders known as the chondrodysplasias. One such disorder, multiple epiphyseal dysplasia (MED), is characterized by mild dwarfism and early-onset osteoarthritis and can result from mutations in the gene encoding matrilin-3 (MATN3). To determine the disease mechanisms that underpin the pathophysiology of MED we generated a murine model of epiphyseal dysplasia by knocking-in a matn3 mutation. Mice that are homozygous for the mutation develop a progressive dysplasia and have short-limbed dwarfism that is consistent in severity with the relevant human phenotype. Mutant matrilin-3 is retained within the rough endoplasmic reticulum of chondrocytes and is associated with an unfolded protein response. Eventually, there is reduced proliferation and spatially dysregulated apoptosis of chondrocytes in the cartilage growth plate, which is likely to be the cause of disrupted linear bone growth and the resulting short-limbed dwarfism in the mutant mice.


Assuntos
Apoptose , Cartilagem/metabolismo , Condrócitos/citologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/fisiologia , Mutação , Osteocondrodisplasias/metabolismo , Animais , Proliferação de Células , Condrócitos/metabolismo , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Proteínas Matrilinas , Camundongos , Camundongos Transgênicos , Modelos Genéticos , Chaperonas Moleculares/metabolismo
4.
Hum Mutat ; 25(6): 593-4, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15880723

RESUMO

Pseudoachondroplasia (PSACH) and some forms of multiple epiphyseal dysplasia (MED) result from mutations in the gene encoding cartilage oligomeric matrix protein (COMP). COMP is a large pentameric glycoprotein found predominantly in the extracellular matrix of cartilage, tendon, and ligament. As a modular protein, it is composed of a coiled-coil domain, four type II (T2) repeats, eight type III (T3) repeats, and a large globular C-terminal domain (CTD). The majority (>85%) of COMP mutations causing PSACH or MED are found in the exons encoding the T3 repeats, and the disease mechanism has been characterised in detail. Much less is known about disease-causing mutations in the CTD; in 10 years only seven mutations have been identified. In this study, we describe eight novel and two recurrent mutations that we have recently identified in patients with PSACH or MED. Interestingly, these mutations result in a spectrum of disease, ranging from mild MED to severe PSACH. Mapping of all known COMP CTD mutations on a three-dimensional model of the C-terminal domain shows that the CTD mutations cluster in two distinct regions. These regions are probably important in stabilising the T3-CTD structure and mediating intra- or intermolecular interactions.


Assuntos
Acondroplasia/genética , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/genética , Glicoproteínas/química , Glicoproteínas/genética , Mutação/genética , Fenótipo , Acondroplasia/diagnóstico por imagem , Proteína de Matriz Oligomérica de Cartilagem , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons/genética , Humanos , Proteínas Matrilinas , Modelos Moleculares , Radiografia
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