Proceedings of the National Academy of Sciences, 1992
DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-... more DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in approximately 80% of French families with this form of diabetes. We previously identified a nonsense mutation in exon 7 in one of these families and showed that it was the likely cause of glucose intolerance in this dominantly inherited disorder. Here we report the isolation and partial sequence of the human glucokinase gene and the identification of two missense mutations in exon 7, Thr-228----Met and Gly-261----Arg, that cosegregate with early-onset non-insulin-dependent diabetes mellitus. To assess the molecular mechanism by which mutations at these two sites may affect glucokinase activity, the crystal structure of the related yeast hexokinase B was used as a simple model for human beta-cell glucokinase. Computer-assisted modeling suggests that mutation of Thr-228 affects affinity for ATP and mutation of Gly-261 may alter glucose bindi...
Background: Genetic mutations causing autosomal recessive Parkinson's disease account for a s... more Background: Genetic mutations causing autosomal recessive Parkinson's disease account for a significant proportion of patients with early-onset disease. However, no large multicentre studies of known recessive Parkinson's disease-linked genes have been performed, to guide genetic testing according to age at onset, family history, ethnic origin, or phenotype. We aimed to evaluate the relative frequencies of mutations in genes causing recessive Parkinson's disease and their associated phenotypes in a large series of European and North African cases. Methods: Clinical data for 1664 patients were collected between 1990 and 2018 from 511 families with recessive Parkinson's disease and/or with consanguinity, and 1098 isolated cases. All the recessively inherited genes were screened by Sanger and/or targeted next-generation sequencing and gene dosage methods. Clinical features were compared between patients with PRKN and those without mutations, by regression analyses adjusted for sex, age at onset, disease duration and levodopa medication. Findings: Biallelic mutations of genes known to cause recessive Parkinson's disease were found in 246 of the 1609 index cases (15·3%): 150 familial (29·4%) and 96 (8·7%) isolated cases. The most frequently mutated genes were PRKN, in 199 cases (12·4%), PINK1, in 23 (1·8%), and DJ-1, in two (0·16%). We screened 675 index cases by targeted sequencing, and 22 were found to have mutations in genes known to cause atypical parkinsonism (3·3%). PRKN and PINK1 mutation frequencies were higher in early-onset (≤40 years) than late-onset Parkinson's disease. The frequency of PRKN mutations in the 1609 index cases decreased with increasing age at onset, from 38% in cases ≤20 years to 4·4% in those with onset at 41 to 60 years. No mutation of PRKN or another recessive Parkinson's disease gene was found in patients with onset above 60. PRKN mutations were more frequent in Caucasians (13·4%) than in North Africans (7·4%). Conversely, PINK1 mutations were more frequent in North Africans (6·3%) than in Caucasians (0·9%). PRKN patients had an earlier age at onset, lower levels of asymmetry, akinesia, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. Interpretation: This is a large study providing information about the frequency of recessive Parkinson's disease genes according to age at onset, family history, ethnic origin, and associated phenotype. Its findings will be useful for genetic testing and counselling. Funding Statement: Fondation de France, France-Parkinson Association, la Federation pour la Recherche sur le Cerveau, the French program "Investissements d'avenir", National Institute for Health Research. Declaration of Interests: SL reports grants from Fondation de France, the French program “Investissements d’avenir” (ANR-10-IAIHU-06), both outside the scope of the submitted work. MA reports grants and personal fees from Abbvie, Teva, Aguettant, Actelion Pharmaceuticals, personal fees from Johnson and Johnson, Merz, Orkyn, all outside the scope of the submitted work. ER reports grants, personal fees and non-financial support from Orkyn, Aguettant, Merz pharma, Everpharma, personal fees and non-financial support from Movement Disorders Society, grants and non-financial support from Elivie, non-financial support from Merck, Dystonia Coalition, Dystonia Medical Research Foundation, grants from Ipsen, Fondation Desmarest, Fonds de dotation Brou de Lauriere, Agence Nationale de la Recherche, AMADYS, personal fees from Medday pharma, Retrophin, European Academy of Neurology, International Association of Parkinsonism and related Disorders, all outside the submitted work. CT received fees from ALLERGAN and from MERZ. J-CC reports grants from Sanofi, personal fees from EverPharma, Denali, BrainEver, Theranexus, Air Liquide, all outside the scope of this work. EB reports grants from Medtronic France, Abbvie, UCB, and Aguettant laboratories but no conflict of interest nor financial concerns about the present research paper submitted for publication. AB reports grants from ANR - Agence nationale de recherche, ARNN - Association pour la Recherche en Neuro-imagerie et Neuropsychologie, France Parkinson, AP-HP, FMR - Fondation Maladies Rares (ex GIS), France Parkinson + FRC (Federation pour la Recherche sur le Cerveau), Universite Mohammed V - Rabat, Prix Allianz Institut de France, RDS (Roger de Spoelberch Foundation), FDF -Fondation de France-, all outside the submitted work. All other authors have no competing interests to declare. Ethics Approval Statement: Informed consent was obtained from all participants, and genetic studies were approved by local ethics committees (INSERM, CCPPRB du Groupe Hospitalier Pitie-Salpetriere, Paris, France).
Parkinson’s disease (PD) is a common and incurable neurodegenerative disease, affecting 1% of the... more Parkinson’s disease (PD) is a common and incurable neurodegenerative disease, affecting 1% of the population over the age of 65 [...]
Parkinson’s disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigi... more Parkinson’s disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigidity, resting tremor) related to loss of dopaminergic neurons mainly in the Substantia nigra pars compacta. Diagnosis is often made after a substantial loss of neurons has already occurred, and while dopamine replacement therapies improve symptoms, they do not modify the course of the disease. Although some biological mechanisms involved in the disease have been identified, such as oxidative stress and accumulation of misfolded proteins, they do not explain entirely PD pathophysiology, and a need for a better understanding remains. Neurodegenerative diseases, including PD, appear to be the result of complex interactions between genetic and environmental factors. The latter can alter gene expression by causing epigenetic changes, such as DNA methylation, post-translational modification of histones and non-coding RNAs. Regulation of genes responsible for monogenic forms of PD may be involv...
Autosomal recessive early-onset parkinsonism is clinically and genetically heterogeneous. Mutatio... more Autosomal recessive early-onset parkinsonism is clinically and genetically heterogeneous. Mutations of three genes, PRKN, PINK1, and DJ-1 cause pure phenotypes usually characterized by levodopa-responsive Parkinson's disease. By contrast, mutations of other genes, including ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, VPS13C, and PTRHD1, cause rarer, more severe diseases with a poor response to levodopa, generally with additional atypical features. We performed data mining on a gene panel or whole-exome sequencing in 460 index cases with early-onset (≤ 40 years) Parkinson's disease, including 57 with autosomal recessive disease and 403 isolated cases. We identified two isolated cases carrying biallelic mutations of SYNJ1 (double-heterozygous p.D791fs/p.Y232H and homozygous p. Y832C mutations) and two siblings with the recurrent homozygous p.R258Q mutation. All four variants were absent or rare in the Genome Aggregation Database, were predicted to be deleterious on in silico analys...
Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are re... more Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene‐targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ‐1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab‐Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa‐induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843–850
Proceedings of the National Academy of Sciences, 1992
DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-... more DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in approximately 80% of French families with this form of diabetes. We previously identified a nonsense mutation in exon 7 in one of these families and showed that it was the likely cause of glucose intolerance in this dominantly inherited disorder. Here we report the isolation and partial sequence of the human glucokinase gene and the identification of two missense mutations in exon 7, Thr-228----Met and Gly-261----Arg, that cosegregate with early-onset non-insulin-dependent diabetes mellitus. To assess the molecular mechanism by which mutations at these two sites may affect glucokinase activity, the crystal structure of the related yeast hexokinase B was used as a simple model for human beta-cell glucokinase. Computer-assisted modeling suggests that mutation of Thr-228 affects affinity for ATP and mutation of Gly-261 may alter glucose bindi...
Background: Genetic mutations causing autosomal recessive Parkinson's disease account for a s... more Background: Genetic mutations causing autosomal recessive Parkinson's disease account for a significant proportion of patients with early-onset disease. However, no large multicentre studies of known recessive Parkinson's disease-linked genes have been performed, to guide genetic testing according to age at onset, family history, ethnic origin, or phenotype. We aimed to evaluate the relative frequencies of mutations in genes causing recessive Parkinson's disease and their associated phenotypes in a large series of European and North African cases. Methods: Clinical data for 1664 patients were collected between 1990 and 2018 from 511 families with recessive Parkinson's disease and/or with consanguinity, and 1098 isolated cases. All the recessively inherited genes were screened by Sanger and/or targeted next-generation sequencing and gene dosage methods. Clinical features were compared between patients with PRKN and those without mutations, by regression analyses adjusted for sex, age at onset, disease duration and levodopa medication. Findings: Biallelic mutations of genes known to cause recessive Parkinson's disease were found in 246 of the 1609 index cases (15·3%): 150 familial (29·4%) and 96 (8·7%) isolated cases. The most frequently mutated genes were PRKN, in 199 cases (12·4%), PINK1, in 23 (1·8%), and DJ-1, in two (0·16%). We screened 675 index cases by targeted sequencing, and 22 were found to have mutations in genes known to cause atypical parkinsonism (3·3%). PRKN and PINK1 mutation frequencies were higher in early-onset (≤40 years) than late-onset Parkinson's disease. The frequency of PRKN mutations in the 1609 index cases decreased with increasing age at onset, from 38% in cases ≤20 years to 4·4% in those with onset at 41 to 60 years. No mutation of PRKN or another recessive Parkinson's disease gene was found in patients with onset above 60. PRKN mutations were more frequent in Caucasians (13·4%) than in North Africans (7·4%). Conversely, PINK1 mutations were more frequent in North Africans (6·3%) than in Caucasians (0·9%). PRKN patients had an earlier age at onset, lower levels of asymmetry, akinesia, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. Interpretation: This is a large study providing information about the frequency of recessive Parkinson's disease genes according to age at onset, family history, ethnic origin, and associated phenotype. Its findings will be useful for genetic testing and counselling. Funding Statement: Fondation de France, France-Parkinson Association, la Federation pour la Recherche sur le Cerveau, the French program "Investissements d'avenir", National Institute for Health Research. Declaration of Interests: SL reports grants from Fondation de France, the French program “Investissements d’avenir” (ANR-10-IAIHU-06), both outside the scope of the submitted work. MA reports grants and personal fees from Abbvie, Teva, Aguettant, Actelion Pharmaceuticals, personal fees from Johnson and Johnson, Merz, Orkyn, all outside the scope of the submitted work. ER reports grants, personal fees and non-financial support from Orkyn, Aguettant, Merz pharma, Everpharma, personal fees and non-financial support from Movement Disorders Society, grants and non-financial support from Elivie, non-financial support from Merck, Dystonia Coalition, Dystonia Medical Research Foundation, grants from Ipsen, Fondation Desmarest, Fonds de dotation Brou de Lauriere, Agence Nationale de la Recherche, AMADYS, personal fees from Medday pharma, Retrophin, European Academy of Neurology, International Association of Parkinsonism and related Disorders, all outside the submitted work. CT received fees from ALLERGAN and from MERZ. J-CC reports grants from Sanofi, personal fees from EverPharma, Denali, BrainEver, Theranexus, Air Liquide, all outside the scope of this work. EB reports grants from Medtronic France, Abbvie, UCB, and Aguettant laboratories but no conflict of interest nor financial concerns about the present research paper submitted for publication. AB reports grants from ANR - Agence nationale de recherche, ARNN - Association pour la Recherche en Neuro-imagerie et Neuropsychologie, France Parkinson, AP-HP, FMR - Fondation Maladies Rares (ex GIS), France Parkinson + FRC (Federation pour la Recherche sur le Cerveau), Universite Mohammed V - Rabat, Prix Allianz Institut de France, RDS (Roger de Spoelberch Foundation), FDF -Fondation de France-, all outside the submitted work. All other authors have no competing interests to declare. Ethics Approval Statement: Informed consent was obtained from all participants, and genetic studies were approved by local ethics committees (INSERM, CCPPRB du Groupe Hospitalier Pitie-Salpetriere, Paris, France).
Parkinson’s disease (PD) is a common and incurable neurodegenerative disease, affecting 1% of the... more Parkinson’s disease (PD) is a common and incurable neurodegenerative disease, affecting 1% of the population over the age of 65 [...]
Parkinson’s disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigi... more Parkinson’s disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigidity, resting tremor) related to loss of dopaminergic neurons mainly in the Substantia nigra pars compacta. Diagnosis is often made after a substantial loss of neurons has already occurred, and while dopamine replacement therapies improve symptoms, they do not modify the course of the disease. Although some biological mechanisms involved in the disease have been identified, such as oxidative stress and accumulation of misfolded proteins, they do not explain entirely PD pathophysiology, and a need for a better understanding remains. Neurodegenerative diseases, including PD, appear to be the result of complex interactions between genetic and environmental factors. The latter can alter gene expression by causing epigenetic changes, such as DNA methylation, post-translational modification of histones and non-coding RNAs. Regulation of genes responsible for monogenic forms of PD may be involv...
Autosomal recessive early-onset parkinsonism is clinically and genetically heterogeneous. Mutatio... more Autosomal recessive early-onset parkinsonism is clinically and genetically heterogeneous. Mutations of three genes, PRKN, PINK1, and DJ-1 cause pure phenotypes usually characterized by levodopa-responsive Parkinson's disease. By contrast, mutations of other genes, including ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, VPS13C, and PTRHD1, cause rarer, more severe diseases with a poor response to levodopa, generally with additional atypical features. We performed data mining on a gene panel or whole-exome sequencing in 460 index cases with early-onset (≤ 40 years) Parkinson's disease, including 57 with autosomal recessive disease and 403 isolated cases. We identified two isolated cases carrying biallelic mutations of SYNJ1 (double-heterozygous p.D791fs/p.Y232H and homozygous p. Y832C mutations) and two siblings with the recurrent homozygous p.R258Q mutation. All four variants were absent or rare in the Genome Aggregation Database, were predicted to be deleterious on in silico analys...
Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are re... more Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene‐targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ‐1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab‐Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa‐induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843–850
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