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Alexandra Durr - One of the best experts on this subject based on the ideXlab platform.
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alteration of ornithine metabolism leads to dominant and recessive hereditary spastic Paraplegia
Brain, 2015Co-Authors: Marie Coutelier, Alexandre Dionnelaporte, Cyril Goizet, Juliette Konop, Perrine Charles, Sara Morais, Florence Habarou, Marion Stoll, Alexandra Durr, Maxime JacoupyAbstract:Hereditary spastic Paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic Paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic Paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1 -related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic Paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes. * Abbreviations : HSP : hereditary spastic Paraplegia P5CS : delta-1-pyrroline-5-carboxylate synthase
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Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic Paraplegia.
Brain : a journal of neurology, 2015Co-Authors: Marie Coutelier, Alexandre Dionne-laporte, Cyril Goizet, Juliette Konop, Sara Morais, Florence Habarou, Marion Stoll, Alexandra Durr, Perrine CharlesAbstract:Hereditary spastic Paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic Paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic Paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1-related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic Paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes.
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cyp7b1 mutations in pure and complex forms of hereditary spastic Paraplegia type 5
Brain, 2009Co-Authors: Amir Boukhris, Jeremy Truchetto, Cyril Goizet, Christian Beetz, Christelle Tesson, Alexandra DurrAbstract:Thirty-four different loci for hereditary spastic Paraplegias have been mapped, and 16 responsible genes have been identified. Autosomal recessive forms of spastic Paraplegias usually have clinically complex phenotypes but the SPG5, SPG24 and SPG28 loci are considered to be associated with ‘pure’ forms of the disease. Very recently, five mutations in the CYP7B1 gene, encoding a cytochrome P450 oxysterol 7-α hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exon–intron boundaries of the CYP7B1 gene by direct sequencing in a series of 82 unrelated autosomal recessive hereditary spastic Paraplegia index patients, manifesting either a pure ( n = 52) or a complex form ( n = 30) of the disease, and in 90 unrelated index patients with sporadic pure hereditary spastic Paraplegia. We identified eight, including six novel, mutations in CYP7B1 segregating in nine families. Three of these mutations were nonsense (p.R63X, p.R112X, p.Y275X) and five were missense mutations (p.T297A, p.R417H, p.R417C, p.F470I, p.R486C), the last four clustering in exon 6 at the C-terminal end of the protein. Residue R417 appeared as a mutational hot-spot. The mean age at onset in 16 patients was 16.4 ± 12.1 years (range 4–47 years). After a mean disease duration of 28.3 ± 13.4 years (10–58), spasticity and functional handicap were moderate to severe in all cases. Interestingly, hereditary spastic Paraplegia was pure in seven SPG5 families but complex in two. In addition, white matter hyperintensities were observed on brain magnetic resonance imaging in three patients issued from two of the seven pure families. Lastly, the index case of one family had a chronic autoimmune hepatitis while his eldest brother died from cirrhosis and liver failure. Whether this association is fortuitous remains unsolved, however. The frequency of CYP7B1 mutations were 7.3% ( n = 6/82) in our series of autosomal recessive hereditary spastic Paraplegia families and 3.3% ( n = 3/90) in our series of sporadic pure spastic Paraplegia. The recent identification of CYP7B1 as the gene responsible for SPG5 highlights a novel molecular mechanism involved in hereditary spastic Paraplegia determinism.
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atlastin1 mutations are frequent in young onset autosomal dominant spastic Paraplegia
JAMA Neurology, 2004Co-Authors: Alexandra Durr, Chantal M E Tallaksen, Agnes Camuzat, Emilie Colin, Didier Hannequin, Paula Coutinho, Bertrand Fontaine, Annick Rossi, R Gil, Christophe RousselleAbstract:Background Hereditary spastic Paraplegias are disorders that are very heterogeneous, both clinically and genetically. The atlastin1 gene has recently been implicated in SPG3A, a form of autosomal dominant pure spastic Paraplegia. Atlastin1 mutations have been identified in 8 families so far. Objectives To determine the relative frequency, phenotype, and mutation spectrum of SPG3A in patients with pure autosomal dominant spastic Paraplegia and onset before age 20 years. Patients and Methods We sequenced the atlastin1 gene in a large series of patients (31 families) in which mutations in the spastin gene, corresponding to the frequent SPG4 locus, had previously been excluded. The phenotype was compared with 126 SPG4 patients. Results We identified 12 families (39%) including 34 patients with 9 different missense atlastin1 mutations, 7 of which are newly described. The main clinical characteristic of these SPG3A patients was pure spasticity with very young onset of symptoms (mean age, 4.6 ± 3.9 years) and slow progression. However, additional signs such as decreased vibration sense and wasting in lower limbs, sphincter disturbances, and scoliosis were found in a minority of patients. In addition, several gene carriers were clinically affected but still asymptomatic (n = 5) or had no clinical signs (n = 2), indicating incomplete penetrance. Compared with patients from other families meeting the same diagnostic criteria (43 patients) and families with SPG4 (126 patients), the major form of autosomal dominant spastic Paraplegia, SPG3A patients had earlier symptom onset, less frequently increased reflexes in the upper limbs, decreased vibration sense in the lower limbs, and fewer sphincter disturbances, but more frequently observed wasting in the lower limbs and scoliosis. These particularities, as well as frequent abnormal motor evoked potentials, could help identify patients to be screened for atlastin1 gene mutations. Conclusions This study enables us to estimate the frequency of the SPG3A mutations in France at 39% in families with young-onset autosomal dominant spastic Paraplegia after exclusion of SPG4 cases. So far, most mutations have been private, although they were all found in exons 7, 8, 12, and 13. These exons should be given priority when performing molecular diagnoses for SPG3A.
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recent advances in hereditary spastic Paraplegia
Current Opinion in Neurology, 2001Co-Authors: Chantal M E Tallaksen, Alexandra Durr, Alexis BriceAbstract:: The hereditary spastic Paraplegias are a group of rare disorders that are characterized by great clinical and genetic heterogeneity. There has been an exponential increase in the number of HSP loci mapped in recent years, with nine out of the 17 loci reported during the past 2 years. Eight loci have now been identified for the autosomal-dominant form, and seven of these are associated with pure HSP. Spastic Paraplegia-4 remains the most frequent locus, and is usually associated with a pure phenotype. Although the corresponding spastin gene was only recently identified, over 50 mutations have been described to date, which renders molecular diagnosis difficult. Five loci are known for autosomal-recessive HSP, and four of these are associated with complex forms, all with different phenotypes. Two genes have been identified: paraplegin and sacsin. Finally, three loci have been identified in X-linked HSP, two of which are complex forms. The genes that encode L1 and PLP were the first to be identified in HSP disorders. Surprisingly, the five genes encode proteins of different families, making understanding and diagnosis of HSP even more difficult. The discovery of new genes should hopefully help to clarify the pathophysiology of these disorders.
Elena I. Rugarli - One of the best experts on this subject based on the ideXlab platform.
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alternative splicing of spg7 a gene involved in hereditary spastic Paraplegia encodes a variant of paraplegin targeted to the endoplasmic reticulum
PLOS ONE, 2012Co-Authors: Giuseppe Mancuso, Esther Barth, Pietro Crivello, Elena I. RugarliAbstract:BACKGROUND: Hereditary spastic Paraplegia defines a group of genetically heterogeneous diseases characterized by weakness and spasticity of the lower limbs owing to retrograde degeneration of corticospinal axons. One autosomal recessive form of the disease is caused by mutation in the SPG7 gene. Paraplegin, the product of SPG7, is a component of the m-AAA protease, a high molecular weight complex that resides in the mitochondrial inner membrane, and performs crucial quality control and biogenesis functions in mitochondria. PRINCIPAL FINDINGS: Here we show the existence in the mouse of a novel isoform of paraplegin, which we name paraplegin-2, encoded by alternative splicing of Spg7 through usage of an alternative first exon. Paraplegin-2 lacks the mitochondrial targeting sequence, and is identical to the mature mitochondrial protein. Remarkably, paraplegin-2 is targeted to the endoplasmic reticulum. We find that paraplegin-2 exposes the catalytic domains to the lumen of the endoplasmic reticulum. Moreover, endogenous paraplegin-2 accumulates in microsomal fractions prepared from mouse brain and retina. Finally, we show that the previously generated mouse model of Spg7-linked hereditary spastic Paraplegia is an isoform-specific knock-out, in which mitochondrial paraplegin is specifically ablated, while expression of paraplegin-2 is retained. CONCLUSIONS/SIGNIFICANCE: These data suggest a possible additional role of AAA proteases outside mitochondria and open the question of their implication in neurodegeneration.
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alternative splicing of spg7 a gene involved in hereditary spastic Paraplegia encodes a variant of paraplegin targeted to the endoplasmic reticulum
PLOS ONE, 2012Co-Authors: Giuseppe Mancuso, Esther Barth, Pietro Crivello, Elena I. RugarliAbstract:BACKGROUND: Hereditary spastic Paraplegia defines a group of genetically heterogeneous diseases characterized by weakness and spasticity of the lower limbs owing to retrograde degeneration of corticospinal axons. One autosomal recessive form of the disease is caused by mutation in the SPG7 gene. Paraplegin, the product of SPG7, is a component of the m-AAA protease, a high molecular weight complex that resides in the mitochondrial inner membrane, and performs crucial quality control and biogenesis functions in mitochondria. PRINCIPAL FINDINGS: Here we show the existence in the mouse of a novel isoform of paraplegin, which we name paraplegin-2, encoded by alternative splicing of Spg7 through usage of an alternative first exon. Paraplegin-2 lacks the mitochondrial targeting sequence, and is identical to the mature mitochondrial protein. Remarkably, paraplegin-2 is targeted to the endoplasmic reticulum. We find that paraplegin-2 exposes the catalytic domains to the lumen of the endoplasmic reticulum. Moreover, endogenous paraplegin-2 accumulates in microsomal fractions prepared from mouse brain and retina. Finally, we show that the previously generated mouse model of Spg7-linked hereditary spastic Paraplegia is an isoform-specific knock-out, in which mitochondrial paraplegin is specifically ablated, while expression of paraplegin-2 is retained. CONCLUSIONS/SIGNIFICANCE: These data suggest a possible additional role of AAA proteases outside mitochondria and open the question of their implication in neurodegeneration.
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variable and tissue specific subunit composition of mitochondrial m aaa protease complexes linked to hereditary spastic Paraplegia
Molecular and Cellular Biology, 2007Co-Authors: Mirko Koppen, Metodi Dimitrov Metodiev, Elena I. Rugarli, Giorgio Casari, Thomas LangerAbstract:The m-AAA protease, an ATP-dependent proteolytic complex in the mitochondrial inner membrane, controls protein quality and regulates ribosome assembly, thus exerting essential housekeeping functions within mitochondria. Mutations in the m-AAA protease subunit paraplegin cause axonal degeneration in hereditary spastic Paraplegia (HSP), but the basis for the unexpected tissue specificity is not understood. Paraplegin assembles with homologous Afg3l2 subunits into hetero-oligomeric complexes which can substitute for yeast m-AAA proteases, demonstrating functional conservation. The function of a third paralogue, Afg3l1 expressed in mouse, is unknown. Here, we analyze the assembly of paraplegin into m-AAA complexes and monitor consequences of paraplegin deficiency in HSP fibroblasts and in a mouse model for HSP. Our findings reveal variability in the assembly of m-AAA proteases in mitochondria in different tissues. Homo-oligomeric Afg3l1 and Afg3l2 complexes and hetero-oligomeric assemblies of both proteins with paraplegin can be formed. Yeast complementation studies demonstrate the proteolytic activity of these assemblies. Paraplegin deficiency in HSP does not result in the loss of m-AAA protease activity in brain mitochondria. Rather, homo-oligomeric Afg3l2 complexes accumulate, and these complexes can substitute for housekeeping functions of paraplegin-containing m-AAA complexes. We therefore propose that the formation of m-AAA proteases with altered substrate specificities leads to axonal degeneration in HSP.
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intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic Paraplegia
Journal of Clinical Investigation, 2005Co-Authors: Marinella Pirozzi, Gennaro Andolfi, Giorgia Dina, Angelo Quattrini, Alberto Auricchio, Maria Chiara Malaguti, Elena I. RugarliAbstract:Degeneration of peripheral motor axons is a common feature of several debilitating diseases including complicated forms of hereditary spastic Paraplegia. One such form is caused by loss of the mitochondrial energy-dependent protease paraplegin. Paraplegin-deficient mice display a progressive degeneration in several axonal tracts, characterized by the accumulation of morphological abnormal mitochondria. We show that adenoassociated virus–mediated (AAV-mediated) intramuscular delivery of paraplegin halted the progression of neuropathological changes and rescued mitochondrial morphology in the peripheral nerves of paraplegin-deficient mice. One single injection before onset of symptoms improved the motor performance of paraplegin-deficient mice for up to 10 months, indicating that the peripheral neuropathy contributes to the clinical phenotype. This study provides a proof of principle that gene transfer may be an effective therapeutic option for patients with paraplegin deficiency and demonstrates that AAV vectors can be successfully employed for retrograde delivery of an intracellular protein to spinal motor neurons, opening new perspectives for several hereditary axonal neuropathies of the peripheral nerves.
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the m aaa protease defective in hereditary spastic Paraplegia controls ribosome assembly in mitochondria
Cell, 2005Co-Authors: Mark Nolden, Mirko Koppen, Sarah Ehses, Elena I. Rugarli, Andrea Bernacchia, Thomas LangerAbstract:Summary AAA proteases comprise a conserved family of membrane bound ATP-dependent proteases that ensures the quality control of mitochondrial inner-membrane proteins. Inactivation of AAA proteases causes pleiotropic phenotypes in various organisms, including respiratory deficiencies, mitochondrial morphology defects, and axonal degeneration in hereditary spastic Paraplegia (HSP). The molecular basis of these defects, however, remained unclear. Here, we describe a regulatory role of an AAA protease for mitochondrial protein synthesis in yeast. The mitochondrial ribosomal protein MrpL32 is processed by the m -AAA protease, allowing its association with preassembled ribosomal particles and completion of ribosome assembly in close proximity to the inner membrane. Maturation of MrpL32 and mitochondrial protein synthesis are also impaired in a HSP mouse model lacking the m -AAA protease subunit paraplegin, demonstrating functional conservation. Our findings therefore rationalize mitochondrial defects associated with m -AAA protease mutants in yeast and shed new light on the mechanism of axonal degeneration in HSP.
H Schuler - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of the atpase domain of the human aaa protein paraplegin spg7
PLOS ONE, 2009Co-Authors: T Karlberg, Susanne Van Den Berg, Martin Hammarstrom, J Sagemark, Ida Johansson, L Holmbergschiavone, H SchulerAbstract:Paraplegin is an m-AAA protease of the mitochondrial inner membrane that is linked to hereditary spastic Paraplegias. The gene encodes an FtsH-homology protease domain in tandem with an AAA+ homology ATPase domain. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA-domain to deliver substrate peptides to its protease domain. We present the crystal structure of the AAA-domain of human paraplegin bound to ADP at 2.2 A. This enables assignment of the roles of specific side chains within the catalytic cycle, and provides the structural basis for understanding the mechanism of disease mutations.
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crystal structure of the atpase domain of the human aaa protein paraplegin spg7
PLOS ONE, 2009Co-Authors: T Karlberg, Martin Hammarstrom, J Sagemark, Ida Johansson, L Holmbergschiavone, Susanne Van Den Berg, H SchulerAbstract:Paraplegin is an m-AAA protease of the mitochondrial inner membrane that is linked to hereditary spastic Paraplegias. The gene encodes an FtsH-homology protease domain in tandem with an AAA+ homology ATPase domain. The protein is believed to form a hexamer that uses ATPase-driven conformational changes in its AAA-domain to deliver substrate peptides to its protease domain. We present the crystal structure of the AAA-domain of human paraplegin bound to ADP at 2.2 A. This enables assignment of the roles of specific side chains within the catalytic cycle, and provides the structural basis for understanding the mechanism of disease mutations. Enhanced version This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
Giorgio Casari - One of the best experts on this subject based on the ideXlab platform.
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Haploinsufficiency of AFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration
The Journal of Neuroscience, 2009Co-Authors: Francesca Maltecca, Raffaealla Magnoni, Federica Cerri, Angelo Quattrini, Giorgio CasariAbstract:Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 complexes in the inner mitochondrial membrane, named m -AAA proteases. These complexes ensure protein quality control in the inner membrane, jointly with a chaperone-like activity on the respiratory chain complexes. Despite coassembling in the same complex, mutations of either paraplegin or AFG3L2 cause two different neurodegenerative disorders. Indeed, mutations of paraplegin are responsible for a recessive form of hereditary spastic Paraplegia, whereas mutations of AFG3L2 have been recently associated to a dominant form of spinocerebellar ataxia (SCA28). In this work, we report that the mouse model haploinsufficient for Afg3l2 recapitulates important pathophysiological features of the human disease, thus representing the first SCA28 model. Furthermore, we propose a pathogenetic mechanism in which respiratory chain dysfunction and increased reactive oxygen species production caused by Afg3l2 haploinsufficiency lead to dark degeneration of Purkinje cells and cerebellar dysfunction.
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variable and tissue specific subunit composition of mitochondrial m aaa protease complexes linked to hereditary spastic Paraplegia
Molecular and Cellular Biology, 2007Co-Authors: Mirko Koppen, Metodi Dimitrov Metodiev, Elena I. Rugarli, Giorgio Casari, Thomas LangerAbstract:The m-AAA protease, an ATP-dependent proteolytic complex in the mitochondrial inner membrane, controls protein quality and regulates ribosome assembly, thus exerting essential housekeeping functions within mitochondria. Mutations in the m-AAA protease subunit paraplegin cause axonal degeneration in hereditary spastic Paraplegia (HSP), but the basis for the unexpected tissue specificity is not understood. Paraplegin assembles with homologous Afg3l2 subunits into hetero-oligomeric complexes which can substitute for yeast m-AAA proteases, demonstrating functional conservation. The function of a third paralogue, Afg3l1 expressed in mouse, is unknown. Here, we analyze the assembly of paraplegin into m-AAA complexes and monitor consequences of paraplegin deficiency in HSP fibroblasts and in a mouse model for HSP. Our findings reveal variability in the assembly of m-AAA proteases in mitochondria in different tissues. Homo-oligomeric Afg3l1 and Afg3l2 complexes and hetero-oligomeric assemblies of both proteins with paraplegin can be formed. Yeast complementation studies demonstrate the proteolytic activity of these assemblies. Paraplegin deficiency in HSP does not result in the loss of m-AAA protease activity in brain mitochondria. Rather, homo-oligomeric Afg3l2 complexes accumulate, and these complexes can substitute for housekeeping functions of paraplegin-containing m-AAA complexes. We therefore propose that the formation of m-AAA proteases with altered substrate specificities leads to axonal degeneration in HSP.
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loss of m aaa protease in mitochondria causes complex i deficiency and increased sensitivity to oxidative stress in hereditary spastic Paraplegia
Journal of Cell Biology, 2003Co-Authors: Luigia Atorino, Roberto Marconi, Mirko Koppen, Laura Cassina, Andrea Ballabio, Thomas Langer, Laura Silvestri, Giorgio CasariAbstract:Mmutations in paraplegin, a putative mitochondrial metallopeptidase of the AAA family, cause an autosomal recessive form of hereditary spastic Paraplegia (HSP). Here, we analyze the function of paraplegin at the cellular level and characterize the phenotypic defects of HSP patients' cells lacking this protein. We demonstrate that paraplegin coassembles with a homologous protein, AFG3L2, in the mitochondrial inner membrane. These two proteins form a high molecular mass complex, which we show to be aberrant in HSP fibroblasts. The loss of this complex causes a reduced complex I activity in mitochondria and an increased sensitivity to oxidant stress, which can both be rescued by exogenous expression of wild-type paraplegin. Furthermore, complementation studies in yeast demonstrate functional conservation of the human paraplegin–AFG3L2 complex with the yeast m-AAA protease and assign proteolytic activity to this structure. These results shed new light on the molecular pathogenesis of HSP and functionally link AFG3L2 to this neurodegenerative disease.
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identification and characterization of yme1l1 a novel paraplegin related gene
Genomics, 1999Co-Authors: Massimiliano Coppola, Alessandro Pizzigoni, Giorgio Casari, Sandro Banfi, Maria Teresa Bassi, Barbara IncertiAbstract:Abstract We recently identified a gene responsible for an autosomal recessive form of hereditary spastic Paraplegia (HSP). This gene encodes paraplegin, a mitochondrial protein highly homologous to the yeast mitochondrial ATPases Afg3p and Rcalp, which have both proteolytic and chaperone-like activities at the inner mitochondrial membrane. By screening the Expressed Sequence Tag database, we identified and characterized a novel human cDNA, ATPase family gene 3-like 2 (AFG3L2, Human Gene Nomenclature Committee-approved symbol), which is closely related to paraplegin. This cDNA encodes a 797-amino-acid predicted protein highly similar to paraplegin as well as to yeast Afg3p and Rca1p. Immunofluorescence studies revealed that AFG3L2 and paraplegin share a similar expression pattern and the same subcellular localization, the mitochondrial compartment. We subsequently mapped AFG3L2 to chromosome 18p11 by radiation hybrid analysis. AFG3L2 may represent a candidate gene for other forms of HSPs and possibly for other neurodegenerative disorders.
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identification and characterization of yme1l1 a novel paraplegin related gene
Genomics, 1999Co-Authors: Massimiliano Coppola, Alessandro Pizzigoni, Giorgio Casari, Sandro Banfi, Maria Teresa Bassi, Barbara IncertiAbstract:Abstract We recently identified a gene responsible for an autosomal recessive form of hereditary spastic Paraplegia (HSP). This gene encodes paraplegin, a mitochondrial protein highly homologous to the yeast mitochondrial ATPases Afg3p and Rcalp, which have both proteolytic and chaperone-like activities at the inner mitochondrial membrane. By screening the Expressed Sequence Tag database, we identified and characterized a novel human cDNA, ATPase family gene 3-like 2 (AFG3L2, Human Gene Nomenclature Committee-approved symbol), which is closely related to paraplegin. This cDNA encodes a 797-amino-acid predicted protein highly similar to paraplegin as well as to yeast Afg3p and Rca1p. Immunofluorescence studies revealed that AFG3L2 and paraplegin share a similar expression pattern and the same subcellular localization, the mitochondrial compartment. We subsequently mapped AFG3L2 to chromosome 18p11 by radiation hybrid analysis. AFG3L2 may represent a candidate gene for other forms of HSPs and possibly for other neurodegenerative disorders.
Cyril Goizet - One of the best experts on this subject based on the ideXlab platform.
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alteration of ornithine metabolism leads to dominant and recessive hereditary spastic Paraplegia
Brain, 2015Co-Authors: Marie Coutelier, Alexandre Dionnelaporte, Cyril Goizet, Juliette Konop, Perrine Charles, Sara Morais, Florence Habarou, Marion Stoll, Alexandra Durr, Maxime JacoupyAbstract:Hereditary spastic Paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic Paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic Paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1 -related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic Paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes. * Abbreviations : HSP : hereditary spastic Paraplegia P5CS : delta-1-pyrroline-5-carboxylate synthase
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Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic Paraplegia.
Brain : a journal of neurology, 2015Co-Authors: Marie Coutelier, Alexandre Dionne-laporte, Cyril Goizet, Juliette Konop, Sara Morais, Florence Habarou, Marion Stoll, Alexandra Durr, Perrine CharlesAbstract:Hereditary spastic Paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic Paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic Paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1-related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic Paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes.
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cyp7b1 mutations in pure and complex forms of hereditary spastic Paraplegia type 5
Brain, 2009Co-Authors: Amir Boukhris, Jeremy Truchetto, Cyril Goizet, Christian Beetz, Christelle Tesson, Alexandra DurrAbstract:Thirty-four different loci for hereditary spastic Paraplegias have been mapped, and 16 responsible genes have been identified. Autosomal recessive forms of spastic Paraplegias usually have clinically complex phenotypes but the SPG5, SPG24 and SPG28 loci are considered to be associated with ‘pure’ forms of the disease. Very recently, five mutations in the CYP7B1 gene, encoding a cytochrome P450 oxysterol 7-α hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exon–intron boundaries of the CYP7B1 gene by direct sequencing in a series of 82 unrelated autosomal recessive hereditary spastic Paraplegia index patients, manifesting either a pure ( n = 52) or a complex form ( n = 30) of the disease, and in 90 unrelated index patients with sporadic pure hereditary spastic Paraplegia. We identified eight, including six novel, mutations in CYP7B1 segregating in nine families. Three of these mutations were nonsense (p.R63X, p.R112X, p.Y275X) and five were missense mutations (p.T297A, p.R417H, p.R417C, p.F470I, p.R486C), the last four clustering in exon 6 at the C-terminal end of the protein. Residue R417 appeared as a mutational hot-spot. The mean age at onset in 16 patients was 16.4 ± 12.1 years (range 4–47 years). After a mean disease duration of 28.3 ± 13.4 years (10–58), spasticity and functional handicap were moderate to severe in all cases. Interestingly, hereditary spastic Paraplegia was pure in seven SPG5 families but complex in two. In addition, white matter hyperintensities were observed on brain magnetic resonance imaging in three patients issued from two of the seven pure families. Lastly, the index case of one family had a chronic autoimmune hepatitis while his eldest brother died from cirrhosis and liver failure. Whether this association is fortuitous remains unsolved, however. The frequency of CYP7B1 mutations were 7.3% ( n = 6/82) in our series of autosomal recessive hereditary spastic Paraplegia families and 3.3% ( n = 3/90) in our series of sporadic pure spastic Paraplegia. The recent identification of CYP7B1 as the gene responsible for SPG5 highlights a novel molecular mechanism involved in hereditary spastic Paraplegia determinism.
