Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk

PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.</p

Étude génétique et corrélation génotype-phénotype de la maladie de Parkinson dans la population tunisienne

Tunisia has been a crossroads of multiple civilizations during successive historical periods including the original Berber population to the Arabs and Europeans. This region is characterized by large pedigrees, low migration rates and high rates of consanguinity that increase the risk of autosomal recessive diseases including neurodegenerative diseases. In our country, the prevalence of Parkinson's disease (PD) increases to 43/100000 person and becomes a major health problem. PD affects more than 2% of adults over the age of 60. It is considered to be the result of the interaction between genetic and environmental factors. During the last 20 years, several genes have been linked to hereditary forms of PD in patients who developed their first symptoms before the age of 40. Our findings showed that the Tunisian population is distinct from other populations, as it is striking that more than 50% of all cases have a genetic origin. The frequency of monogenic forms in patients with late onset PD was relatively high and similar to that of patients with early onset. These forms were mainly due to the mutation LRRK2-p.G2019S (identified in 44.4% of cases). We confirmed that this mutation is a founder mutation appeared in a single common ancestor of Berber origin. Clinically, we showed that patients with the LRRK2-p.G2019S mutation had an earlier onset of PD, but with a more benign phenotype than idiopathic. A second founder mutation with a Berber origin (p.Q456*) was identified in the PINK1 gene. The unusual high frequency of mutations in this gene may be limited to the Tunisian Berber population. Our results also confirmed that mutations in the PARK2 gene and the GBA gene do not constitute a frequent risk factor for PD in Tunisia. In addition to these mutations on known genes, we have identified 4 new candidate genes in PD. This particular genetic structure of PD in Tunisia could be mainly the result of the historical Berber origin of our Tunisian population.La Tunisie a vu une grande variété d'envahisseurs et de migrants allant de la population berbère autochtone aux Arabes et Européens. Cette région est caractérisée par les grands pedigrees, les faibles taux de migration et les taux élevés de consanguinité qui augmentent le risque des maladies autosomiques récessives y compris les maladies neuro-dégénératives. Dans notre pays, la prévalence de la maladie de Parkinson (MP) augmente jusqu’à 43/100000 personnes et devient un problème de santé majeur. La MP est une maladie neuro-dégénérative dont la forme idiopathique débute en moyenne vers 60 ans. Au cours des 20 dernières années, plusieurs gènes ont été identifiés chez des patients qui ont développé leurs premiers symptômes avant l’âge de 40 ans. Notre étude a montré que la structure génétique de la MP en Tunisie est distincte des autres populations, puisque plus de 50% des cas avaient une origine génétique. La fréquence des formes monogéniques chez les patients avec un âge de début tardif de la MP était relativement élevée et similaire à celle des patients avec un âge de début précoce. Ces formes étaient essentiellement dues à la mutation LRRK2-p.G2019S (identifiée chez 44.4% des cas) qui s'avère être une mutation fondatrice apparue chez un seul ancêtre commun d’origine berbère. Sur le plan clinique, nous avons montré que les patients porteurs de la mutation LRRK2-p.G2019S avaient un âge de début de la MP plus précoce mais avec un phénotype plus bénin que celui des formes idiopathiques. Une deuxième mutation fondatrice d’origine berbère (p.Q456*) a été identifiée sur le gène PINK1. La fréquence élevée inhabituelle des mutations sur ce gène peut être limitée à la population tunisienne berbère. Nos résultats ont aussi confirmé que les mutations sur le gène PARK2 et sur le gène GBA ne constituent pas un facteur de risque fréquent de la MP en Tunisie. En plus de ces mutations sur les gènes connus, nous avons identifié 4 nouveaux gènes candidats dans la MP. Cette structure génétique particulière de la MP en Tunisie pourrait être principalement le résultat de l'origine historique berbère de notre population Tunisienne

Clinical and genetic caracterization of Parkinson’s disease in Tunisian population

La Tunisie a vu une grande variété d'envahisseurs et de migrants allant de la population berbère autochtone aux Arabes et Européens. Cette région est caractérisée par les grands pedigrees, les faibles taux de migration et les taux élevés de consanguinité qui augmentent le risque des maladies autosomiques récessives y compris les maladies neuro-dégénératives. Dans notre pays, la prévalence de la maladie de Parkinson (MP) augmente jusqu’à 43/100000 personnes et devient un problème de santé majeur. La MP est une maladie neuro-dégénérative dont la forme idiopathique débute en moyenne vers 60 ans. Au cours des 20 dernières années, plusieurs gènes ont été identifiés chez des patients qui ont développé leurs premiers symptômes avant l’âge de 40 ans. Notre étude a montré que la structure génétique de la MP en Tunisie est distincte des autres populations, puisque plus de 50% des cas avaient une origine génétique. La fréquence des formes monogéniques chez les patients avec un âge de début tardif de la MP était relativement élevée et similaire à celle des patients avec un âge de début précoce. Ces formes étaient essentiellement dues à la mutation LRRK2-p.G2019S (identifiée chez 44.4% des cas) qui s'avère être une mutation fondatrice apparue chez un seul ancêtre commun d’origine berbère. Sur le plan clinique, nous avons montré que les patients porteurs de la mutation LRRK2-p.G2019S avaient un âge de début de la MP plus précoce mais avec un phénotype plus bénin que celui des formes idiopathiques. Une deuxième mutation fondatrice d’origine berbère (p.Q456*) a été identifiée sur le gène PINK1. La fréquence élevée inhabituelle des mutations sur ce gène peut être limitée à la population tunisienne berbère. Nos résultats ont aussi confirmé que les mutations sur le gène PARK2 et sur le gène GBA ne constituent pas un facteur de risque fréquent de la MP en Tunisie. En plus de ces mutations sur les gènes connus, nous avons identifié 4 nouveaux gènes candidats dans la MP. Cette structure génétique particulière de la MP en Tunisie pourrait être principalement le résultat de l'origine historique berbère de notre population Tunisienne.Tunisia has been a crossroads of multiple civilizations during successive historical periods including the original Berber population to the Arabs and Europeans. This region is characterized by large pedigrees, low migration rates and high rates of consanguinity that increase the risk of autosomal recessive diseases including neurodegenerative diseases. In our country, the prevalence of Parkinson's disease (PD) increases to 43/100000 person and becomes a major health problem. PD affects more than 2% of adults over the age of 60. It is considered to be the result of the interaction between genetic and environmental factors. During the last 20 years, several genes have been linked to hereditary forms of PD in patients who developed their first symptoms before the age of 40. Our findings showed that the Tunisian population is distinct from other populations, as it is striking that more than 50% of all cases have a genetic origin. The frequency of monogenic forms in patients with late onset PD was relatively high and similar to that of patients with early onset. These forms were mainly due to the mutation LRRK2-p.G2019S (identified in 44.4% of cases). We confirmed that this mutation is a founder mutation appeared in a single common ancestor of Berber origin. Clinically, we showed that patients with the LRRK2-p.G2019S mutation had an earlier onset of PD, but with a more benign phenotype than idiopathic. A second founder mutation with a Berber origin (p.Q456*) was identified in the PINK1 gene. The unusual high frequency of mutations in this gene may be limited to the Tunisian Berber population. Our results also confirmed that mutations in the PARK2 gene and the GBA gene do not constitute a frequent risk factor for PD in Tunisia. In addition to these mutations on known genes, we have identified 4 new candidate genes in PD. This particular genetic structure of PD in Tunisia could be mainly the result of the historical Berber origin of our Tunisian population

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson’s disease

International audienceThe LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n ¼ 724) and meta-analyzed our data with previously published data (n ¼ 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk

PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alphasynuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability.We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster.We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A(p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus.In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment.We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration