pedro Brites - Academia.edu (original) (raw)

Papers by pedro Brites

Research paper thumbnail of Mutational Analysis of an X-Linked Adrenoleukodystrophy (ALD) Patient with Detectable ALD Protein

Annals of The New York Academy of Sciences, 1996

Research paper thumbnail of Peroxisomes, lipid metabolism and lipotoxicity

Biochimica Et Biophysica Acta-molecular and Cell Biology of Lipids, 2010

Research paper thumbnail of Functions and biosynthesis of plasmalogens in health and disease

Biochimica Et Biophysica Acta-molecular and Cell Biology of Lipids, 2004

Research paper thumbnail of Mutational Spectrum in the PEX7 Gene and Functional Analysis of Mutant Alleles in 78 Patients with Rhizomelic Chondrodysplasia Punctata Type 1

American Journal of Human Genetics, 2002

Rhizomelic chondrodysplasia punctata (RCDP) is a genetically heterogeneous, autosomal recessive d... more Rhizomelic chondrodysplasia punctata (RCDP) is a genetically heterogeneous, autosomal recessive disorder of peroxisomal metabolism that is clinically characterized by symmetrical shortening of the proximal long bones, cataracts, periarticular calcifications, multiple joint contractures, and psychomotor retardation. Most patients with RCDP have mutations in the PEX7 gene encoding peroxin 7, the cytosolic PTS2-receptor protein required for targeting a subset of enzymes to peroxisomes. These enzymes are deficient in cells of patients with RCDP, because of their mislocalization to the cytoplasm. We report the mutational spectrum in the PEX7 gene of 78 patients (including five pairs of sibs) clinically and biochemically diagnosed with RCDP type I. We found 22 different mutations, including 18 novel ones. Furthermore, we show by functional analysis that disease severity correlates with PEX7 allele activity: expression of eight different alleles from patients with severe RCDP failed to restore the targeting defect in RCDP fibroblasts, whereas two alleles found only in patients with mild disease complemented the targeting defect upon overexpression. Surprisingly, one of the mild alleles comprises a duplication of nucleotides 45–52, which is predicted to lead to a frameshift at codon 17 and an absence of functional peroxin 7. The ability of this allele to complement the targeting defect in RCDP cells suggests that frame restoration occurs, resulting in full-length functional peroxin 7, which leads to amelioration of the predicted severe phenotype. This was confirmed in vitro by expression of the eight-nucleotide duplication–containing sequence fused in different reading frames to the coding sequence of firefly luciferase in COS cells.

Research paper thumbnail of Molecular basis of rhizomelic chondrodysplasia punctata type I: High frequency of the Leu292 Stop mutation in 38 patients

Nucleic Acids Research, 1998

Research paper thumbnail of Plasmalogens participate in very-long-chain fatty acid-induced pathology

Research paper thumbnail of The mouse as a model to understand peroxisomal biogenesis and its disorders

Drug Discovery Today: Disease Models, 2004

Research paper thumbnail of Rhizomelic chondrodysplasia punctata is a peroxisomal protein trageting disease caused by a non-functional PTS2 receptor

Research paper thumbnail of Comparative profiling of the peroxisomal proteome of wildtype and Pex7 knockout mice by quantitative mass spectrometry

International Journal of Mass Spectrometry

Research paper thumbnail of Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata

Journal of Endocrinological Investigation, 2003

Research paper thumbnail of Identification of PEX7 as the Second Gene Involved in Refsum Disease

American Journal of Human Genetics, 2003

Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficie... more Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH). In most patients with RD, disease-causing mutations in the PHYH gene have been identified, but, in a subset, no mutations could be found, indicating that the condition is genetically heterogeneous. Linkage analysis of a few patients diagnosed with RD, but without mutations in PHYH, suggested a second locus on chromosome 6q22-24. This region includes the PEX7 gene, which codes for the peroxin 7 receptor protein required for peroxisomal import of proteins containing a peroxisomal targeting signal type 2. Mutations in PEX7 normally cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder. Biochemical analyses of the patients with RD revealed defects not only in phytanic acid alpha-oxidation but also in plasmalogen synthesis and peroxisomal thiolase. Furthermore, we identified mutations in the PEX7 gene. Our data show that mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD and that clinical diagnosis of conditions involving retinitis pigmentosa, ataxia, and polyneuropathy may require a full screen of peroxisomal functions.

Research paper thumbnail of Plasmalogens participate in very-long-chain fatty acid-induced pathology

Publications of The Astronomical Society of Japan, 2009

Research paper thumbnail of Biosynthesis of ether-phospholipids including plasmalogens, peroxisomes and human disease: new insights into an old problem

Clinical Lipidology, 2010

Ether-phospholipids represent an important subclass of phospholipids in animal cell membranes cha... more Ether-phospholipids represent an important subclass of phospholipids in animal cell membranes characterized by the presence of an ether bond at the sn-I position and the enrichment of PUFAs at the sn-2 position. Of the different ether-phospholipids, plasmalogens are the most abundant form and their importance to human health is emphasized by the severe clinical presentation of patients with defects in

Research paper thumbnail of Peroxisomes, Refsum's disease and the alpha- and omega-oxidation of phytanic acid

Chemistry and Physics of Lipids, 2009

In the present paper, we describe the current state of knowledge regarding the enzymology of the ... more In the present paper, we describe the current state of knowledge regarding the enzymology of the phytanic acid alpha-oxidation pathway. The product of phytanic acid alpha-oxidation, i.e. pristanic acid, undergoes three cycles of beta-oxidation in peroxisomes after which the products, including 4,8-dimethylnonanoyl-CoA, propionyl-CoA and acetyl-CoA, are exported from the peroxisome via one of two routes, including (i) the carnitine-dependent route, mediated by CRAT (carnitine acetyltransferase) and CROT (carnitine O-octanoyltransferase), and (ii) the free acid route, mediated by one or more of the peroxisomal ACOTs (acyl-CoA thioesterases). We also describe our recent data on the omega-oxidation of phytanic acid, especially since pharmacological up-regulation of this pathway may form the basis of a new treatment strategy for ARD (adult Refsum's disease). In patients suffering from ARD, phytanic acid accumulates in tissues and body fluids due to a defect in the alpha-oxidation system.

Research paper thumbnail of Ataxia with loss of Purkinje cells in a mouse model for Refsum disease

Proceedings of The National Academy of Sciences, 2008

Research paper thumbnail of Mutational Analysis of an X-Linked Adrenoleukodystrophy (ALD) Patient with Detectable ALD Protein

Annals of The New York Academy of Sciences, 1996

Research paper thumbnail of Peroxisomes, lipid metabolism and lipotoxicity

Biochimica Et Biophysica Acta-molecular and Cell Biology of Lipids, 2010

Research paper thumbnail of Functions and biosynthesis of plasmalogens in health and disease

Biochimica Et Biophysica Acta-molecular and Cell Biology of Lipids, 2004

Research paper thumbnail of Mutational Spectrum in the PEX7 Gene and Functional Analysis of Mutant Alleles in 78 Patients with Rhizomelic Chondrodysplasia Punctata Type 1

American Journal of Human Genetics, 2002

Rhizomelic chondrodysplasia punctata (RCDP) is a genetically heterogeneous, autosomal recessive d... more Rhizomelic chondrodysplasia punctata (RCDP) is a genetically heterogeneous, autosomal recessive disorder of peroxisomal metabolism that is clinically characterized by symmetrical shortening of the proximal long bones, cataracts, periarticular calcifications, multiple joint contractures, and psychomotor retardation. Most patients with RCDP have mutations in the PEX7 gene encoding peroxin 7, the cytosolic PTS2-receptor protein required for targeting a subset of enzymes to peroxisomes. These enzymes are deficient in cells of patients with RCDP, because of their mislocalization to the cytoplasm. We report the mutational spectrum in the PEX7 gene of 78 patients (including five pairs of sibs) clinically and biochemically diagnosed with RCDP type I. We found 22 different mutations, including 18 novel ones. Furthermore, we show by functional analysis that disease severity correlates with PEX7 allele activity: expression of eight different alleles from patients with severe RCDP failed to restore the targeting defect in RCDP fibroblasts, whereas two alleles found only in patients with mild disease complemented the targeting defect upon overexpression. Surprisingly, one of the mild alleles comprises a duplication of nucleotides 45–52, which is predicted to lead to a frameshift at codon 17 and an absence of functional peroxin 7. The ability of this allele to complement the targeting defect in RCDP cells suggests that frame restoration occurs, resulting in full-length functional peroxin 7, which leads to amelioration of the predicted severe phenotype. This was confirmed in vitro by expression of the eight-nucleotide duplication–containing sequence fused in different reading frames to the coding sequence of firefly luciferase in COS cells.

Research paper thumbnail of Molecular basis of rhizomelic chondrodysplasia punctata type I: High frequency of the Leu292 Stop mutation in 38 patients

Nucleic Acids Research, 1998

Research paper thumbnail of Plasmalogens participate in very-long-chain fatty acid-induced pathology

Research paper thumbnail of The mouse as a model to understand peroxisomal biogenesis and its disorders

Drug Discovery Today: Disease Models, 2004

Research paper thumbnail of Rhizomelic chondrodysplasia punctata is a peroxisomal protein trageting disease caused by a non-functional PTS2 receptor

Research paper thumbnail of Comparative profiling of the peroxisomal proteome of wildtype and Pex7 knockout mice by quantitative mass spectrometry

International Journal of Mass Spectrometry

Research paper thumbnail of Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata

Journal of Endocrinological Investigation, 2003

Research paper thumbnail of Identification of PEX7 as the Second Gene Involved in Refsum Disease

American Journal of Human Genetics, 2003

Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficie... more Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH). In most patients with RD, disease-causing mutations in the PHYH gene have been identified, but, in a subset, no mutations could be found, indicating that the condition is genetically heterogeneous. Linkage analysis of a few patients diagnosed with RD, but without mutations in PHYH, suggested a second locus on chromosome 6q22-24. This region includes the PEX7 gene, which codes for the peroxin 7 receptor protein required for peroxisomal import of proteins containing a peroxisomal targeting signal type 2. Mutations in PEX7 normally cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder. Biochemical analyses of the patients with RD revealed defects not only in phytanic acid alpha-oxidation but also in plasmalogen synthesis and peroxisomal thiolase. Furthermore, we identified mutations in the PEX7 gene. Our data show that mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD and that clinical diagnosis of conditions involving retinitis pigmentosa, ataxia, and polyneuropathy may require a full screen of peroxisomal functions.

Research paper thumbnail of Plasmalogens participate in very-long-chain fatty acid-induced pathology

Publications of The Astronomical Society of Japan, 2009

Research paper thumbnail of Biosynthesis of ether-phospholipids including plasmalogens, peroxisomes and human disease: new insights into an old problem

Clinical Lipidology, 2010

Ether-phospholipids represent an important subclass of phospholipids in animal cell membranes cha... more Ether-phospholipids represent an important subclass of phospholipids in animal cell membranes characterized by the presence of an ether bond at the sn-I position and the enrichment of PUFAs at the sn-2 position. Of the different ether-phospholipids, plasmalogens are the most abundant form and their importance to human health is emphasized by the severe clinical presentation of patients with defects in

Research paper thumbnail of Peroxisomes, Refsum's disease and the alpha- and omega-oxidation of phytanic acid

Chemistry and Physics of Lipids, 2009

In the present paper, we describe the current state of knowledge regarding the enzymology of the ... more In the present paper, we describe the current state of knowledge regarding the enzymology of the phytanic acid alpha-oxidation pathway. The product of phytanic acid alpha-oxidation, i.e. pristanic acid, undergoes three cycles of beta-oxidation in peroxisomes after which the products, including 4,8-dimethylnonanoyl-CoA, propionyl-CoA and acetyl-CoA, are exported from the peroxisome via one of two routes, including (i) the carnitine-dependent route, mediated by CRAT (carnitine acetyltransferase) and CROT (carnitine O-octanoyltransferase), and (ii) the free acid route, mediated by one or more of the peroxisomal ACOTs (acyl-CoA thioesterases). We also describe our recent data on the omega-oxidation of phytanic acid, especially since pharmacological up-regulation of this pathway may form the basis of a new treatment strategy for ARD (adult Refsum's disease). In patients suffering from ARD, phytanic acid accumulates in tissues and body fluids due to a defect in the alpha-oxidation system.

Research paper thumbnail of Ataxia with loss of Purkinje cells in a mouse model for Refsum disease

Proceedings of The National Academy of Sciences, 2008