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1.
Biochim Biophys Acta Mol Basis Dis ; 1866(1): 165573, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672551

RESUMO

Mice homozygous for the human GRACILE syndrome mutation (Bcs1lc.A232G) display decreased respiratory chain complex III activity, liver dysfunction, hypoglycemia, rapid loss of white adipose tissue and early death. To assess the underlying mechanism of the lipodystrophy in homozygous mice (Bcs1lp.S78G), these and wild-type control mice were subjected to a short 4-hour fast. The homozygotes had low baseline blood glucose values, but a similar decrease in response to fasting as in wild-type mice, resulting in hypoglycemia in the majority. Despite the already depleted glycogen and increased triacylglycerol content in the mutant livers, the mice responded to fasting by further depletion and increase, respectively. Increased plasma free fatty acids (FAs) upon fasting suggested normal capacity for mobilization of lipids from white adipose tissue into circulation. Strikingly, however, serum glycerol concentration was not increased concomitantly with free FAs, suggesting its rapid uptake into the liver and utilization for fuel or gluconeogenesis in the mutants. The mutant hepatocyte mitochondria were capable of responding to fasting by appropriate morphological changes, as analyzed by electron microscopy, and by increasing respiration. Mutants showed increased hepatic gene expression of major metabolic controllers typically associated with fasting response (Ppargc1a, Fgf21, Cd36) already in the fed state, suggesting a chronic starvation-like metabolic condition. Despite this, the mutant mice responded largely normally to fasting by increasing hepatic respiration and switching to FA utilization, indicating that the mechanisms driving these adaptations are not compromised by the CIII dysfunction. SUMMARY STATEMENT: Bcs1l mutant mice with severe CIII deficiency, energy deprivation and post-weaning lipolysis respond to fasting similarly to wild-type mice, suggesting largely normal systemic lipid mobilization and utilization mechanisms.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Jejum/fisiologia , Mobilização Lipídica/fisiologia , Acidose Láctica/metabolismo , Animais , Glicemia/metabolismo , Colestase/metabolismo , Transporte de Elétrons/fisiologia , Feminino , Retardo do Crescimento Fetal/metabolismo , Gluconeogênese/fisiologia , Glicogênio/metabolismo , Hemossiderose/metabolismo , Hepatócitos/metabolismo , Hepatócitos/fisiologia , Homozigoto , Hipoglicemia/metabolismo , Hipoglicemia/fisiopatologia , Fígado/metabolismo , Fígado/fisiologia , Masculino , Erros Inatos do Metabolismo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Doenças Mitocondriais/congênito , Doenças Mitocondriais/metabolismo , Aminoacidúrias Renais/metabolismo , Triglicerídeos/metabolismo
2.
Front Immunol ; 9: 508, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29616026

RESUMO

Lysinuric protein intolerance (LPI) is a recessively inherited aminoaciduria caused by mutations of SLC7A7, the gene encoding y+LAT1 light chain of system y+L for cationic amino acid transport. The pathogenesis of LPI is still unknown. In this study, we have utilized a gene silencing approach in macrophages and airway epithelial cells to investigate whether complications affecting lung and immune system are directly ascribable to the lack of SLC7A7 or, rather, mediated by an abnormal accumulation of arginine in mutated cells. When SLC7A7/y+LAT1 was silenced in human THP-1 macrophages and A549 airway epithelial cells by means of short interference RNA (siRNA), a significant induction of the expression and release of the inflammatory mediators IL1ß and TNFα was observed, no matter the intracellular arginine availability. This effect was mainly regulated at transcriptional level through the activation of NFκB signaling pathway. Moreover, since respiratory epithelial cells are the important sources of chemokines in response to pro-inflammatory stimuli, the effect of IL1ß has been addressed on SLC7A7 silenced A549 cells. Results obtained indicated that the downregulation of SLC7A7/y+LAT1 markedly strengthened the stimulatory effect of the cytokine on CCL5/RANTES expression and release without affecting the levels of CXCL8/IL8. Consistently, also the conditioned medium of silenced THP-1 macrophages activated airway epithelial cells in terms of CCL5/RANTES expression due to the presence of elevated amount of proinflammatory cytokines. In conclusion, our results point to a novel thus far unknown function of SLC7A7/y+LAT1, that, under physiological conditions, besides transporting arginine, may act as a brake to restrain inflammation.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/imunologia , Cadeias Leves da Proteína-1 Reguladora de Fusão/metabolismo , Inflamação/imunologia , Macrófagos/imunologia , Aminoacidúrias Renais/imunologia , Mucosa Respiratória/imunologia , Células A549 , Erros Inatos do Metabolismo dos Aminoácidos/genética , Quimiocina CCL5/metabolismo , Cadeias Leves da Proteína-1 Reguladora de Fusão/genética , Inativação Gênica , Humanos , Inflamação/genética , Interleucina-1beta/metabolismo , Mutação/genética , NF-kappa B/metabolismo , Fenótipo , RNA Interferente Pequeno/genética , Aminoacidúrias Renais/genética , Células THP-1 , Fator de Necrose Tumoral alfa/metabolismo
3.
Orphanet J Rare Dis ; 12(1): 73, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-28427446

RESUMO

BACKGROUND: Mitochondrial diseases due to defective respiratory chain complex III (CIII) are relatively uncommon. The assembly of the eleven-subunit CIII is completed by the insertion of the Rieske iron-sulfur protein, a process for which BCS1L protein is indispensable. Mutations in the BCS1L gene constitute the most common diagnosed cause of CIII deficiency, and the phenotypic spectrum arising from mutations in this gene is wide. RESULTS: A case of CIII deficiency was investigated in depth to assess respiratory chain function and assembly, and brain, skeletal muscle and liver histology. Exome sequencing was performed to search for the causative mutation(s). The patient's platelets and muscle mitochondria showed respiration defects and defective assembly of CIII was detected in fibroblast mitochondria. The patient was compound heterozygous for two novel mutations in BCS1L, c.306A > T and c.399delA. In the cerebral cortex a specific pattern of astrogliosis and widespread loss of microglia was observed. Further analysis showed loss of Kupffer cells in the liver. These changes were not found in infants suffering from GRACILE syndrome, the most severe BCS1L-related disorder causing early postnatal mortality, but were partially corroborated in a knock-in mouse model of BCS1L deficiency. CONCLUSIONS: We describe two novel compound heterozygous mutations in BCS1L causing CIII deficiency. The pathogenicity of one of the mutations was unexpected and points to the importance of combining next generation sequencing with a biochemical approach when investigating these patients. We further show novel manifestations in brain, skeletal muscle and liver, including abnormality in specialized resident macrophages (microglia and Kupffer cells). These novel phenotypes forward our understanding of CIII deficiencies caused by BCS1L mutations.


Assuntos
Acidose Láctica/genética , Colestase/genética , Retardo do Crescimento Fetal/genética , Hemossiderose/genética , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/congênito , Aminoacidúrias Renais/genética , Animais , Transporte de Elétrons/fisiologia , Complexo III da Cadeia de Transporte de Elétrons/genética , Flavoproteínas Transferidoras de Elétrons/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Doenças Mitocondriais/genética , Encefalomiopatias Mitocondriais/genética , Mutação/genética
4.
J Vet Intern Med ; 31(2): 598-603, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28109116

RESUMO

A case study of renal tubular dysfunction consistent with idiopathic Fanconi syndrome is reported in an 18-month-old Holstein heifer. The clinical, biochemical, and histopathological features are described. The heifer had clinical signs of growth retardation, wasting, and persistent diarrhea. Biochemical blood analysis identified hypokalemia, hyponatremia, and hypochloremia. Urinalysis identified glycosuria, proteinuria, and acidic pH. Histological examination of the kidney disclosed mild tubular necrosis with proteinaceous casts in the lumina of renal tubules. We performed LC-HRMS on urine to confirm Fanconi syndrome. Using this technique, we identified severe generalized aminoaciduria suggestive of idiopathic renal Fanconi syndrome in this heifer.


Assuntos
Aminoácidos/urina , Doenças dos Bovinos/patologia , Síndrome de Fanconi/veterinária , Aminoacidúrias Renais/veterinária , Animais , Bovinos , Doenças dos Bovinos/etiologia , Síndrome de Fanconi/patologia , Feminino , Necrose do Córtex Renal/etiologia , Necrose do Córtex Renal/veterinária , Aminoacidúrias Renais/etiologia , Aminoacidúrias Renais/urina
5.
Genet Couns ; 27(4): 509-512, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-30226971

RESUMO

GRACILE Syndrome, is an autosomal recessive disease presenting with growth retardation, severe lactic acidosis, Fanconi type tubulopathy, cholestasis, iron overload and early death without any dysmorphological or neurological features. The BCSIL gene mutation is responsible for GRACILE syndrome, Bjornstad syndrome and complex III deficiency. Bjomstad syndrome is characterized by sensorineural hearing loss and abnormal flat twisted hair shafts. The case is GRACILE syndrome with Bjomstad phenotype in neonatal period due to BCSL1 gene mutation.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Acidose Láctica/genética , Colestase/genética , Análise Mutacional de DNA , Complexo III da Cadeia de Transporte de Elétrons/genética , Retardo do Crescimento Fetal/genética , Doenças do Cabelo/genética , Perda Auditiva Neurossensorial/genética , Hemossiderose/genética , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/congênito , Fenótipo , Aminoacidúrias Renais/genética , Acidose/diagnóstico , Acidose/genética , Acidose Láctica/diagnóstico , Colestase/diagnóstico , Consanguinidade , Evolução Fatal , Retardo do Crescimento Fetal/diagnóstico , Doenças do Cabelo/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Hemossiderose/diagnóstico , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/diagnóstico , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Aminoacidúrias Renais/diagnóstico , Turquia
6.
Pediatr Nephrol ; 31(1): 7-14, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25618772

RESUMO

Severe vitamin D deficiency (reduction in serum 25(OH)D concentration) in infants and children can cause features of the Fanconi syndrome, including phosphaturia, glycosuria, aminoaciduria, and renal tubular acidosis. This indicates that vitamin D and its metabolites influence proximal tubule function. Filtered 25(OH)D bound to vitamin D binding protein (DBP) is endocytosed by megalin-cubilin in the apical membrane. Intracellular 25(OH)D is metabolized to 1,25(OH)2D or calcitroic acid by 1-α-hydroxylase or 24-hydroxylase in tubule cell mitochondria. Bone-produced fibroblast growth factor 23 (FGF23) bound to Klotho in tubule cells and intracellular phosphate concentrations are regulators of 1-α-hydroxylase activity and cause proximal tubule phosphaturia. Aminoaciduria occurs when amino acid transporter synthesis is deficient, and 1,25(OH)2D along with retinoic acid up-regulate transporter synthesis by a vitamin D response element in the promoter region of the transporter gene. This review discusses evidence gained from studies in animals or cell lines, as well as from human disorders, that provide insight into vitamin D-proximal tubule interactions.


Assuntos
Túbulos Renais Proximais/metabolismo , Aminoacidúrias Renais/etiologia , Deficiência de Vitamina D/complicações , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Animais , Predisposição Genética para Doença , Humanos , Túbulos Renais Proximais/fisiopatologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Prognóstico , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Aminoacidúrias Renais/genética , Aminoacidúrias Renais/metabolismo , Aminoacidúrias Renais/fisiopatologia , Fatores de Risco , Transdução de Sinais , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/fisiopatologia , Vitamina D3 24-Hidroxilase/genética , Vitamina D3 24-Hidroxilase/metabolismo
7.
Eur J Pediatr ; 175(4): 517-25, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26563427

RESUMO

UNLABELLED: We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like (BCS1L) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debré-Fanconi-type tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A>G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood. CONCLUSION: Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) tubulopathy in the newborn period. WHAT IS KNOWN: • Mutations in BCS1L cause mitochondrial complex III deficiencies. • Phenotypic presentations of defective BCS1L range from Bjornstad to neonatal GRACILE syndrome. What is New: • Description of a novel homozygous mutation in BCS1L with transient neonatal acidosis and persistent de Toni-Debré-Fanconi-type tubulopathy. • The long survival of patients with phenotypic presentation of severe complex III deficiency is uncommon.


Assuntos
Acidose Láctica/genética , Colestase/genética , Surdez/genética , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Síndrome de Fanconi/genética , Retardo do Crescimento Fetal/genética , Hemossiderose/genética , Erros Inatos do Metabolismo/genética , Microcefalia/genética , Doenças Mitocondriais/congênito , Aminoacidúrias Renais/genética , ATPases Associadas a Diversas Atividades Celulares , Adolescente , Adulto , Western Blotting , Diagnóstico Diferencial , Complexo III da Cadeia de Transporte de Elétrons/genética , Eletroforese em Gel de Poliacrilamida , Síndrome de Fanconi/etiologia , Feminino , Transtornos do Crescimento/genética , Homozigoto , Humanos , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Doenças Mitocondriais/genética , Mutação de Sentido Incorreto
8.
Eur J Hum Genet ; 23(9): 1254-8, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25564041

RESUMO

Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 µM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.


Assuntos
Alquil e Aril Transferases/genética , Ataxia/diagnóstico , Ataxia/genética , Mitocôndrias Musculares/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Debilidade Muscular/diagnóstico , Debilidade Muscular/genética , Mutação Puntual , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Acidose Láctica/sangue , Acidose Láctica/genética , Acidose Láctica/patologia , Alquil e Aril Transferases/deficiência , Ataxia/sangue , Ataxia/patologia , Consanguinidade , Evolução Fatal , Feminino , Expressão Gênica , Insuficiência Hepática/sangue , Insuficiência Hepática/genética , Insuficiência Hepática/patologia , Humanos , Recém-Nascido , Deficiência Intelectual/sangue , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mitocôndrias Musculares/enzimologia , Mitocôndrias Musculares/patologia , Doenças Mitocondriais/sangue , Doenças Mitocondriais/patologia , Debilidade Muscular/sangue , Debilidade Muscular/patologia , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Proteinúria/sangue , Proteinúria/genética , Proteinúria/patologia , Aminoacidúrias Renais/sangue , Aminoacidúrias Renais/genética , Aminoacidúrias Renais/patologia , Análise de Sequência de DNA , Ubiquinona/sangue , Ubiquinona/genética
9.
Am J Physiol Renal Physiol ; 306(12): F1462-76, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24761004

RESUMO

The kidney is one of the major loci for the expression of cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CTH). While CBS-deficient (Cbs(-/-)) mice display homocysteinemia/methioninemia and severe growth retardation, and rarely survive beyond the first 4 wk, CTH-deficient (Cth(-/-)) mice show homocysteinemia/cystathioninemia but develop with no apparent abnormality. This study examined renal amino acid reabsorption in those mice. Although both 2-wk-old Cbs(-/-) and Cth(-/-) mice had normal renal architecture, their serum/urinary amino acid profiles largely differed from wild-type mice. The most striking feature was marked accumulation of Met and cystathionine in serum/urine/kidney samples of Cbs(-/-) and Cth(-/-) mice, respectively. Levels of some neutral amino acids (Val, Leu, Ile, and Tyr) that were not elevated in Cbs(-/-) serum were highly elevated in Cbs(-/-) urine, and urinary excretion of other neutral amino acids (except Met) was much higher than expected from their serum levels, demonstrating neutral aminoaciduria in Cbs(-/-) (not Cth(-/-)) mice. Because the bulk of neutral amino acids is absorbed via a B(0)AT1 transporter and Met has the highest substrate affinity for B(0)AT1 than other neutral amino acids, hypermethioninemia may cause hyperexcretion of neutral amino acids.


Assuntos
Aminoácidos Neutros/metabolismo , Cistationina beta-Sintase/deficiência , Homocistinúria/epidemiologia , Homocistinúria/metabolismo , Aminoacidúrias Renais/epidemiologia , Aminoacidúrias Renais/metabolismo , Animais , Comorbidade , Cistationina/metabolismo , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/deficiência , Cistationina gama-Liase/genética , Modelos Animais de Doenças , Feminino , Hiper-Homocisteinemia/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Metionina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
10.
Ren Fail ; 36(6): 953-4, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24655110

RESUMO

GRACILE syndrome is a rare autosomal recessive disease characterized by fetal growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload, profound lactic acidosis, and early death. It is caused by homozygosity for a missense mutation in the BCS1L gene. The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III. Here we report that a homozygous mutation c.296C > T (p.P99L), in the first exon of BCS1L gene found in an affected 2-month-old boy of asymptomatic consanguineous parents results in GRACILE syndrome. This genotype is associated with a severe clinical presentation. So far no available treatments have changed the fatal course of the disease, and the metabolic disturbance responsible is still not clearly identified. Therefore, providing prenatal diagnosis in families with previous affected infants is of major importance. Mitochondrial disorders are an extremely heterogeneous group of diseases sharing, in common, the fact that they all ultimately impair the function of the mitochondrial respiratory chain. A clinical picture with fetal growth restriction, postnatal lactacidosis, aminoaciduria, hypoglycemia, coagulopathy, elevated liver enzymes, and cholestasis should direct investigations on mitochondrial disorder.


Assuntos
Acidose Láctica/genética , Colestase/genética , Complexo III da Cadeia de Transporte de Elétrons/genética , Retardo do Crescimento Fetal/genética , Hemossiderose/genética , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/congênito , Aminoacidúrias Renais/genética , ATPases Associadas a Diversas Atividades Celulares , Humanos , Lactente , Masculino , Doenças Mitocondriais/genética , Mutação de Sentido Incorreto
11.
J Inherit Metab Dis ; 36(5): 813-20, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22991165

RESUMO

Our study describes a novel phenotype in a series of nine Saudi patients with lactic acidosis, from four consanguineous families three of which are related. Detailed genetic studies including linkage, homozygosity mapping and targeted sequencing identified a causative mutation in the BCS1L gene. All affected members of the families have an identical mutation in this gene, mutations of which are recognized causes of Björnstad syndrome, GRACILE syndrome and a syndrome of neonatal tubulopathy, encephalopathy, and liver failure (MIM 606104) leading to isolated mitochondrial respiratory chain complex III deficiency. Here we report the appearance of a novel behavioral (five patients) and psychiatric (two patients) phenotype associated with a p.Gly129Arg BCS1L mutation, differing from the phenotype in a previously reported singleton patient with this mutation. The psychiatric symptoms emanated after childhood, initially as hypomania later evolving into intermittent psychosis. Neuroradiological findings included subtle white matter abnormalities, whilst muscle histopathology and respiratory chain studies confirmed respiratory chain dysfunction. The variable neuro-psychiatric manifestations and cortical visual dysfunction are most unusual and not reported associated with other BCS1L mutations. This report emphasizes the clinical heterogeneity associated with the mutation in BCS1L gene, even within the same family and we recommend that defects in this gene should be considered in the differential diagnosis of lactic acidosis with variable involvement of different organs.


Assuntos
Acidose Láctica/genética , Complexo III da Cadeia de Transporte de Elétrons/genética , Mutação , ATPases Associadas a Diversas Atividades Celulares , Acidose Láctica/metabolismo , Adolescente , Adulto , Criança , Colestase/genética , Colestase/metabolismo , Transporte de Elétrons/genética , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Predisposição Genética para Doença , Doenças do Cabelo/genética , Doenças do Cabelo/metabolismo , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Hemossiderose/genética , Hemossiderose/metabolismo , Homozigoto , Humanos , Masculino , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Doenças Mitocondriais/congênito , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Fenótipo , Aminoacidúrias Renais/genética , Aminoacidúrias Renais/metabolismo
12.
Duodecim ; 128(15): 1560-7, 2012.
Artigo em Finlandês | MEDLINE | ID: mdl-22970607

RESUMO

GRACILE syndrome belongs to the Finnish disease heritage, and is caused by a point mutation in the BCS1L-gene encoding a mitochondrial protein. This leads to dysfunction of the complex III in the respiratory chain. Significant fetal growth disturbance is the primary manifestation. Within the first day the newborn infant develops severe lactic acidosis. Hypoglycemia, elevated serum ferritin and conjugated bilirubin values and aminoaciduria imply mitochondrial liver disease and renal tubulopathy. In Finland, the diagnosis is based on the 232A>G mutation in the BCS1L-gene. No specific treatment is available. GRACILE syndrome leads to early death.


Assuntos
Acidose Láctica/diagnóstico , Colestase/diagnóstico , Retardo do Crescimento Fetal/diagnóstico , Hemossiderose/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Aminoacidúrias Renais/diagnóstico , ATPases Associadas a Diversas Atividades Celulares , Acidose Láctica/epidemiologia , Acidose Láctica/genética , Biomarcadores/sangue , Colestase/epidemiologia , Colestase/genética , Complexo III da Cadeia de Transporte de Elétrons/genética , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/genética , Finlândia/epidemiologia , Hemossiderose/epidemiologia , Hemossiderose/genética , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/congênito , Mutação Puntual , Aminoacidúrias Renais/epidemiologia , Aminoacidúrias Renais/genética
13.
Am J Hematol ; 87(4): 437-9, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22287505
14.
J Inherit Metab Dis ; 34(3): 741-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21484424

RESUMO

For more than a decade now blue native polyacrylamide gel electrophoresis (BN-PAGE) has been used for the study of the oxidative phosphorylation (OXPHOS) complexes. Catalytic activities of complexes I, II, IV and V can be assessed, after separation by gel electrophoresis, by incubation of the BN-PAGE gel in specific staining solutions. However, until now, a reliable staining method for testing ubiquinol cytochrome c oxidoreductase (complex III) activity by BN-PAGE gel techniques was not available. In addition, spectrophotometric methods currently in use for detection of complex III deficiency in patients are not very sensitive. Here, we describe a newly developed diagnostic method for visualization of complex III activity by direct in-gel evaluation of ubiquinol cytochrome oxidoreductase activity. We validated the method by reporting the results in six patients with previously characterised complex III defects.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/química , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Eletroforese em Gel de Poliacrilamida/métodos , Erros Inatos do Metabolismo/metabolismo , Coloração e Rotulagem/métodos , Acidose/metabolismo , Acidose/patologia , Acidose Láctica/metabolismo , Acidose Láctica/patologia , Resinas Acrílicas , Estudos de Casos e Controles , Colestase/metabolismo , Colestase/patologia , Cor , Complexo III da Cadeia de Transporte de Elétrons/análise , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Hemossiderose/metabolismo , Hemossiderose/patologia , Humanos , Fígado/química , Fígado/metabolismo , Fígado/patologia , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/patologia , Doenças Mitocondriais/congênito , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miocárdio/química , Miocárdio/metabolismo , Miocárdio/patologia , Desnaturação Proteica , Aminoacidúrias Renais/metabolismo , Aminoacidúrias Renais/patologia
15.
Am J Med Genet C Semin Med Genet ; 157C(1): 54-62, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21308987

RESUMO

Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid transport at the basolateral membrane of epithelial cells in intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. LPI was initially described in Finland, but has worldwide distribution. Typically, symptoms begin after weaning with refusal of feeding, vomiting, and consequent failure to thrive. Hepatosplenomegaly, hematological anomalies, neurological involvement, including hyperammonemic coma are recurrent clinical features. Two major complications, pulmonary alveolar proteinosis and renal disease are increasingly observed in LPI patients. There is extreme variability in the clinical presentation even within individual families, frequently leading to misdiagnosis or delayed diagnosis. This condition is diagnosed by urine amino acids, showing markedly elevated excretion of lysine and other dibasic amino acids despite low plasma levels of lysine, ornithine, and arginine. The biochemical diagnosis can be uncertain, requiring confirmation by DNA testing. So far, approximately 50 different mutations have been identified in the SLC7A7 gene in a group of 142 patients from 110 independent families. No genotype-phenotype correlation could be established. Therapy requires a low protein diet, low-dose citrulline supplementation, nitrogen-scavenging compounds to prevent hyperammonemia, lysine, and carnitine supplements. Supportive therapy is available for most complications with bronchoalveolar lavage being necessary for alveolar proteinosis.


Assuntos
Rim/metabolismo , Lisina/urina , Aminoacidúrias Renais/genética , Aminoacidúrias Renais/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos Básicos/genética , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Células Epiteliais/metabolismo , Finlândia , Cadeias Leves da Proteína-1 Reguladora de Fusão/genética , Cadeias Leves da Proteína-1 Reguladora de Fusão/metabolismo , Estudos de Associação Genética , Humanos , Mucosa Intestinal/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/genética , Mutação , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/metabolismo , Aminoacidúrias Renais/diagnóstico , Aminoacidúrias Renais/dietoterapia
16.
Hepatology ; 53(2): 437-47, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21274865

RESUMO

UNLABELLED: Mitochondrial dysfunction is an important cause for neonatal liver disease. Disruption of genes encoding oxidative phosphorylation (OXPHOS) components usually causes embryonic lethality, and thus few disease models are available. We developed a mouse model for GRACILE syndrome, a neonatal mitochondrial disease with liver and kidney involvement, caused by a homozygous BCS1L mutation (232A>G). This gene encodes a chaperone required for incorporation of Rieske iron-sulfur protein (RISP) into complex III of respiratory chain. Homozygous mutant mice after 3 weeks of age developed striking similarities to the human disease: growth failure, hepatic glycogen depletion, steatosis, fibrosis, and cirrhosis, as well as tubulopathy, complex III deficiency, lactacidosis, and short lifespan. BCS1L was decreased in whole liver cells and isolated mitochondria of mutants at all ages. RISP incorporation into complex III was diminished in symptomatic animals; however, in young animals complex III was correctly assembled. Complex III activity in liver, heart, and kidney of symptomatic mutants was decreased to 20%, 40%, and 40% of controls, respectively, as demonstrated with electron flux kinetics through complex III. In high-resolution respirometry, CIII dysfunction resulted in decreased electron transport capacity through the respiratory chain under maximum substrate input. Complex I function, suggested to be dependent on a functional complex III, was, however, unaffected. CONCLUSION: We present the first viable model of complex III deficiency mimicking a human mitochondrial disorder. Incorporation of RISP into complex III in young homozygotes suggests another complex III assembly factor during early ontogenesis. The development of symptoms from about 3 weeks of age provides a convenient time window for studying the pathophysiology and treatment of mitochondrial hepatopathy and OXPHOS dysfunction in general.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/deficiência , Hepatopatias/genética , Doenças Mitocondriais/genética , Chaperonas Moleculares/genética , Mutação/genética , ATPases Associadas a Diversas Atividades Celulares , Acidose Láctica/genética , Animais , Colestase/genética , Modelos Animais de Doenças , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Retardo do Crescimento Fetal/genética , Hemossiderose/genética , Homozigoto , Erros Inatos do Metabolismo/genética , Camundongos , Camundongos Mutantes , Fosforilação Oxidativa , Aminoacidúrias Renais/genética
17.
J Clin Invest ; 121(1): 446-53, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21123949

RESUMO

Solute carrier family 1, member 1 (SLC1A1; also known as EAAT3 and EAAC1) is the major epithelial transporter of glutamate and aspartate in the kidneys and intestines of rodents. Within the brain, SLC1A1 serves as the predominant neuronal glutamate transporter and buffers the synaptic release of the excitatory neurotransmitter glutamate within the interneuronal synaptic cleft. Recent studies have also revealed that polymorphisms in SLC1A1 are associated with obsessive-compulsive disorder (OCD) in early-onset patient cohorts. Here we report that SLC1A1 mutations leading to substitution of arginine to tryptophan at position 445 (R445W) and deletion of isoleucine at position 395 (I395del) cause human dicarboxylic aminoaciduria, an autosomal recessive disorder of urinary glutamate and aspartate transport that can be associated with mental retardation. These mutations of conserved residues impeded or abrogated glutamate and cysteine transport by SLC1A1 and led to near-absent surface expression in a canine kidney cell line. These findings provide evidence that SLC1A1 is the major renal transporter of glutamate and aspartate in humans and implicate SLC1A1 in the pathogenesis of some neurological disorders.


Assuntos
Transportador 3 de Aminoácido Excitatório/genética , Mutação , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Linhagem Celular , Análise Mutacional de DNA , Cães , Transportador 3 de Aminoácido Excitatório/química , Transportador 3 de Aminoácido Excitatório/metabolismo , Feminino , Genes Recessivos , Humanos , Técnicas In Vitro , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Rim/metabolismo , Masculino , Modelos Biológicos , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Oócitos/metabolismo , Linhagem , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Aminoacidúrias Renais/genética , Aminoacidúrias Renais/metabolismo , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Xenopus laevis
18.
Chem Biodivers ; 7(6): 1450-8, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20564563

RESUMO

D-amino acid oxidase (DAO) catalyzes oxidative deamination of D-amino acids. Since D-amino acids are considered to be rare in eukaryotes, physiological function of this enzyme has been enigmatic for a long time. Mutant mice lacking DAO were found, and their strain was established. The urine of the mutant mice contained large amounts of D-amino acids. D-Amino acids were also present in their organs and blood. The origin of these D-amino acids was pursued. The results indicate that one of the physiological functions of DAO is the metabolism of D-amino acids of internal and external origin. A large amount of D-serine is shown to exist in the brain of mammals. It binds to the coagonist-binding site of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and enhances the neurotransmission. DAO metabolizes this D-serine and, therefore, modulates neurotransmission. Mutant mice displayed phenotypes resulting from the enhanced NMDA receptor function. Recent studies have shown that DAO is associated with schizophrenia. Mutant mice were resistant to the drugs which act on NMDA receptors and elicit schizophrenia-like symptoms. Recently, mutant rats lacking DAO have also been found. They were free from D-serine-induced nephrotoxicity, indicating involvement of DAO in this toxicity. The mutant mice and rats lacking DAO would be useful for the elucidation of the physiological functions of DAO and the etiology of neuronal diseases associated with DAO.


Assuntos
D-Aminoácido Oxidase/fisiologia , Aminoácidos/sangue , Aminoácidos/urina , Animais , D-Aminoácido Oxidase/genética , Camundongos , Camundongos Mutantes , Ratos , Ratos Mutantes , Receptores de N-Metil-D-Aspartato/metabolismo , Aminoacidúrias Renais/metabolismo , Esquizofrenia/metabolismo
19.
J Pediatr ; 155(1): 94-9, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19559295

RESUMO

OBJECTIVE: To compare the renal and extra-renal phenotypes of patients classified as having Dent disease, Dent-2 disease, or Lowe syndrome. STUDY DESIGN: Chart review of data from 93 patients with identified voltage-gated chloride channel and chloride/proton antiporter 5 gene and oculo-cerebro-renal syndrome of Lowe gene mutations observed by the authors, complemented with published data. RESULTS: There was a wide overlap of renal symptoms. Nephrocalcinosis was more prevalent in Dent-1 disease, and renal tubular acidosis, aminoaciduria, and renal failure was more prevalent in patients with Lowe syndrome. Patients with Lowe syndrome were shorter than patients with Dent-1 disease, and patients with Dent-2 disease showed an intermediate phenotype. Three patients with Dent-2 disease had mild peripheral cataract, and 9 patients were noted to have some degree of mental retardation. CONCLUSION: There is a phenotypic continuum within patients with Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for loss of oculo-cerebro-renal syndrome of Lowe gene function.


Assuntos
Síndrome Oculocerebrorrenal/genética , Erros Inatos do Transporte Tubular Renal/genética , Acidose Tubular Renal/genética , Adolescente , Estatura/genética , Catarata/genética , Criança , Pré-Escolar , Canais de Cloreto/genética , Taxa de Filtração Glomerular , Humanos , Lactente , Deficiência Intelectual/genética , Mutação , Nefrocalcinose/genética , Fenótipo , Monoéster Fosfórico Hidrolases/genética , Aminoacidúrias Renais/genética , Insuficiência Renal/genética , Adulto Jovem
20.
Rheumatol Int ; 30(2): 265-7, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19363610

RESUMO

Abstract A 66-year-old woman showing renal dysfunction with elevated serum alkaline phosphatase and anti-SS-A antibody was admitted. A labial salivary gland biopsy showing infiltration of mononuclear cells and positive anti-SS-A antibody with sicca symptoms led to a diagnosis of primary Sjögren's syndrome (SS). Fanconi's syndrome was diagnosed by renal tubular acidosis along with renal glucosuria or aminoaciduria and multiple bone fractures on bone scintigraphy. Typical bilateral pulmonary shadows were confirmed as organizing pneumonia (OP) determined by the analysis of bronchoalveolar lavage fluid and transbronchial lung biopsy. A rare complication of Fanconi's syndrome with OP in SS is described.


Assuntos
Pneumonia em Organização Criptogênica/diagnóstico , Síndrome de Fanconi/complicações , Fraturas Ósseas/etiologia , Traumatismo Múltiplo/etiologia , Síndrome de Sjogren/complicações , Acidose Tubular Renal/diagnóstico , Acidose Tubular Renal/imunologia , Idoso , Fosfatase Alcalina/sangue , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Pneumonia em Organização Criptogênica/imunologia , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/imunologia , Feminino , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/imunologia , Glicosúria Renal/diagnóstico , Glicosúria Renal/imunologia , Humanos , Monócitos/imunologia , Traumatismo Múltiplo/diagnóstico por imagem , Traumatismo Múltiplo/imunologia , Cintilografia , Aminoacidúrias Renais/diagnóstico , Aminoacidúrias Renais/imunologia , Glândulas Salivares/imunologia , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia
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