ORCID Profile
0000-0002-9048-1041
Current Organisations
University of Amsterdam
,
Universidade Federal de Mato Grosso do Sul
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Publisher: Wiley
Date: 2020
DOI: 10.1002/ACN3.50957
Publisher: Oxford University Press (OUP)
Date: 11-02-2022
DOI: 10.1093/HMG/DDAC040
Abstract: Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical presentations. Here, we report four in iduals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected in iduals had a similar infantile presentation comprising progressive encephalopathy, bull’s eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected in idual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibroblasts from two patients further confirmed the functional defect demonstrating reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol, the substrate of CRLS1. Proteomic profiling of patient cells and mouse Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. These findings support that deleterious variants in CRLS1 cause an autosomal recessive mitochondrial disease, presenting as a severe encephalopathy with multi-systemic involvement. Furthermore, we identify key signatures in cardiolipin and proteome profiles across various degrees of cardiolipin loss, facilitating the use of omics technologies to guide future diagnosis of mitochondrial diseases.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.CELREP.2017.09.008
Abstract: Consumption of a hypercaloric diet upregulates microglial innate immune reactivity along with a higher expression of lipoprotein lipase (Lpl) within the reactive microglia in the mouse brain. Here, we show that knockdown of the Lpl gene specifically in microglia resulted in deficient microglial uptake of lipid, mitochondrial fuel utilization shifting to glutamine, and significantly decreased immune reactivity. Mice with knockdown of the Lpl gene in microglia gained more body weight than control mice on a high-carbohydrate high-fat (HCHF) diet. In these mice, microglial reactivity was significantly decreased in the mediobasal hypothalamus, accompanied by downregulation of phagocytic capacity and increased mitochondrial dysmorphologies. Furthermore, HCHF-diet-induced POMC neuronal loss was accelerated. These results show that LPL-governed microglial immunometabolism is essential to maintain microglial function upon exposure to an HCHF diet. In a hypercaloric environment, lack of such an adaptive immunometabolic response has detrimental effects on CNS regulation of energy metabolism.
Publisher: Oxford University Press (OUP)
Date: 23-04-2002
Publisher: CSIRO Publishing
Date: 06-07-2021
DOI: 10.1071/AN20317
Abstract: Context Integrating trees and pastures can provide benefits to grazing animals in warm climates, such as provision of shade during the excessive heat. Aim Our aim was to evaluate the effects of two arrangements of trees on grass production and behavioural, physiological and blood parameters of crossbred lambs grazing massai grass (Megathyrsus maximus) pastures in a tropical environment in São Paulo state, Brazil. Methods Two groups of 24 Santa Inês × Dorper male lambs (~90 days old, 24.0 ± 3.3 and 22.0 ± 2.4 kg bodyweight, respectively) were used in two growing seasons, stratified by initial bodyweight and randomly assigned to one of three treatments: unshaded massai grass (no shading, NS), moderate shading (MS), or intense shading (IS). Treatments MS and IS were established with single rows of eucalyptus trees at spacing 12 m or 6 m between rows and 2 m within rows, corresponding to 786 and 1190 trees/ha. Each growing season consisted of two grazing cycles of ~20 days each, when tester animals grazed simultaneously in a rotational stocking system with variable stocking rate. Behavioural observations were feeding, lying ruminating, standing ruminating, lying, standing still, searching for food, and other. Physiological measurements were rectal temperature, respiratory frequency and heart rate. Blood parameters included haemogram, acute-phase proteins and serum cortisol concentrations. Key results Animals under treatment IS spent more time (P 0.05) lying, standing still and at other activities than animals under NS and MS. Moreover, they presented lower rectal temperature and respiratory and heart rates than animals under NS during the first growing season, which was the season with higher temperatures. Cortisol and acute-phase proteins were not affected by treatment. Conclusions When animals were exposed to sun, the silvopastoral system was efficient for avoiding heat stress however, the density of trees reduced the forage mass. Implications The silvopastoral system is a viable alternative production system in warm climates to improve the welfare of sheep, but the density of trees must be considered so that it does not negatively influence the forage mass.
Publisher: Wiley
Date: 09-2002
Abstract: Systemic carnitine deficiency (CDSP) (McKusick 212140) is a rare autosomal recessive disease caused by defective plasma membrane uptake of carnitine. The disease is characterized by Reye syndrome, progressive cardiomyopathy, skeletal myopathy, hypoglycaemia and hyperammonaemia. CDSP is a treatable disease provided an early diagnosis is made and prompt treatment with L-carnitine is initiated. The biochemical diagnosis of the disease is based on the findings of very low plasma and tissue carnitine concentrations. Recently, a human gene, SLC22A5, encoding a sodium-dependent high-affinity carnitine transporter OCTN2 was cloned from human kidney and shown to be mutated in systemic carnitine deficiency. Here we report two unrelated Saudi CDSP patients who were detected by tandem mass spectrometric analysis (MS/MS) of blood spots. Studies in skin fibroblasts from the two patients showed a severely reduced carnitine uptake. Subsequent molecular studies led to the identification of two novel missense mutations in the OCTN2 gene in the two patients.
Publisher: Springer Science and Business Media LLC
Date: 10-06-2012
DOI: 10.1038/NG.2325
Abstract: Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking.
Publisher: Elsevier BV
Date: 06-2005
Publisher: Wiley
Date: 28-10-2020
DOI: 10.1002/AJMG.A.61936
No related grants have been discovered for Frederic Vaz.