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Papers by Christelle Tesson

Research paper thumbnail of Intrafamilial and interfamilial heterogeneity of PINK1-associated Parkinson's disease in Sudan

Parkinsonism & Related Disorders

Research paper thumbnail of Identification of a DAGLB Mutation in a Non‐Chinese Patient with Parkinson's Disease

Research paper thumbnail of Combination of Positional Cloning and New Generation Sequencing Identifies 3 Novel Genes in Spastic Paraplegia Involved in Common Metabolic Pathways (P01.205)

Research paper thumbnail of PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

Brain

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involve... more The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signaling 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 > 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 va...

Research paper thumbnail of ELOVL5 Mutations Cause Spinocerebellar Ataxia 38

The American Journal of Human Genetics, 2014

Research paper thumbnail of CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5

Research paper thumbnail of Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice

Research paper thumbnail of Mutations in KCND3 cause spinocerebellar ataxia type 22

Annals of Neurology, 2012

Research paper thumbnail of Alteration of Fatty-Acid-Metabolizing Enzymes Affects Mitochondrial Form and Function in Hereditary Spastic Paraplegia

The American Journal of Human Genetics, 2012

Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous groups of neurolo... more Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous groups of neurological disorders, both clinically and genetically. The disease comprises pure and complex forms that clinically include slowly progressive lower-limb spasticity resulting from degeneration of the corticospinal tract. At least 48 loci accounting for these diseases have been mapped to date, and mutations have been identified in 22 genes, most of which play a role in intracellular trafficking. Here, we identified mutations in two functionally related genes (DDHD1 and CYP2U1) in individuals with autosomal-recessive forms of HSP by using either the classical positional cloning or a combination of whole-genome linkage mapping and next-generation sequencing. Interestingly, three subjects with CYP2U1 mutations presented with a thin corpus callosum, white-matter abnormalities, and/or calcification of the basal ganglia. These genes code for two enzymes involved in fatty-acid metabolism, and we have demonstrated in human cells that the HSP pathophysiology includes alteration of mitochondrial architecture and bioenergetics with increased oxidative stress. Our combined results focus attention on lipid metabolism as a critical HSP pathway with a deleterious impact on mitochondrial bioenergetic function.

Research paper thumbnail of Clinical Variability of SYNJ1-Associated Early-Onset Parkinsonism

Frontiers in Neurology, 2021

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...

Research paper thumbnail of Genetic and Phenotypic Characterisation of Autosomal Recessive Parkinson's Disease in a Large Multicentre Cohort

SSRN Electronic Journal, 2019

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 adjus...

Research paper thumbnail of REPORT ELOVL5 Mutations Cause Spinocerebellar Ataxia 38

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative ... more Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the u3 and u6 series. Arachidoni...

Research paper thumbnail of Correction: Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Genetics in Medicine

The original version of this Article contained an error in the author name for Lionel Van Malderg... more The original version of this Article contained an error in the author name for Lionel Van Maldergem. The family name was incorrectly spelled Van Maldergen. This has now been corrected in both the PDF and HTML versions of the Article.

Research paper thumbnail of Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Genetics in Medicine

Purpose Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebel... more Purpose Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48). Methods We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance. Results STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease–like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) “second hits” in AFG3L2 , PRKCG , and TBP were detected in three families suggesting synergic effects. Conclusion Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

Research paper thumbnail of Lack of evidence for association of UQCRC1 with autosomal dominant Parkinson's disease in Caucasian families

Research paper thumbnail of Segregation of ATP10B variants in families with autosomal recessive parkinsonism

Acta Neuropathologica

Martin et al. [2] recently reported that biallelic missense and stop-gain variants in ATP10B are ... more Martin et al. [2] recently reported that biallelic missense and stop-gain variants in ATP10B are associated with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They identified double-heterozygous variants demonstrated to be located in trans in three of seven isolated cases (six with PD and one with DLB). These variants had a minor allele frequency (MAF) < 5% in the public Genome Aggregation Database (GnomAD) (https ://gnoma d.broad insti tute. org). Using cell function assays, they showed that nine of the ten variants tested resulted in ATPase activity and lipid translocation decreases and a lower level of cell protection against rotenone exposure, consistent with a loss of ATP10B function. Overall, this study indicates that biallelic ATP10B missense variants increase the risk of PD. However, the relatively high frequency of several of these ATP10B variants (> 2%), and the presence of healthy carriers homozygous for these variants in GnomAD raised questions about their pathogenicity. In a large case–control study, Real et al. [3] also questioned the implication of ATP10B variants as risk factors in the pathogenesis of PD. However, in their reply Smolders and Van Broeckhoven [4] pointed out that Real et al. [3] did not assess the phasing and therefore could not conclude that ATP10B was involved in their cohort but agreed that analyses of large number of trios are necessary to estimate the frequency of PD carriers of homozygous or compound heterozygous ATP10B variants. We assessed the presence of biallelic ATP10B variants in families with PD and their segregation with the disease, by analyzing whole-exome sequencing (WES) data from 17 PD families with autosomal recessive (AR) inheritance including at least two affected siblings (Supplementary information for patients and methods). Setting the MAF threshold at 5%, as used in Martin et al.’s paper, we identified six rare ATP10B missense variants, including three previously reported [2], in two of the 17 families. In the consanguineous Algerian FDP-167 family, the reported p.L1421F and p.I540T variants were both present in the three affected siblings, with ages at onset ranging from 30 to 35 years (Fig. 1a). Segregation analysis provided evidence for a cis location of the two variants, both inherited from the mother, who was unaffected at age 58, suggesting that they cannot be causal for PD, given the AR transmission of the disease. In the consanguineous Turkish family PD-IST-154 with typical PD (Supplementary information), the index case (IV-6) carried the p.V219M, p.G671R, and p.N865K variants in the homozygous state. The p.G671R and p.N865K variants have previously been reported to occur in cis [2]. Segregation analysis revealed that the affected sister (IV-4) carried the same variants, but in the heterozygous state, whereas the 52 year-old unaffected sister (IV-5) carried the same three variants in the homozygous state (Fig. 1b). As expected, both unaffected parents were heterozygous carriers of the three variants, whereas the father (III-1) carried another rare missense variant, p.T1019S, on the same haplotype. Segregation analysis alone is sufficient to exclude these variants as the cause of PD within this family. Moreover, we previously identified a homozygous p.L34R mutation in FBXO7 that segregated with the disease in this family (Fig. 1b) [1]. This variant is Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0040 1-020-02219 -6) contains supplementary material, which is available to authorized users.

Research paper thumbnail of Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

Frontiers in Neurology

LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (... more LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were Lesage et al. Characterization of Dominant Parkinson's Disease screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2-2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.

Research paper thumbnail of Characterization of Recessive Parkinson Disease in a Large Multicenter Study

Annals of Neurology

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

Research paper thumbnail of Gene Panel Sequencing Identifies Novel Pathogenic Mutations in Moroccan Patients with Familial Parkinson Disease

Journal of Molecular Neuroscience

In the past two decades, genetic studies of familial forms of Parkinson’s disease (PD) have shown... more In the past two decades, genetic studies of familial forms of Parkinson’s disease (PD) have shown evidence that PD has a significant genetic component. Indeed, 12 genes are strongly involved in PD causality, three of them having dominant inheritance and 9 causing early-onset autosomal recessive forms, including 3 with a typical PD and 6 with an atypical parkinsonism. The aim of this study was to determine the genetic basis of familial PD in Moroccan patients. We selected 18 Moroccan index case with familial forms of PD. Patients were first screened for exon-rearrangements by MLPA kit. They were then analyzed by gene panel next-generation sequencing (NGS). Functional variants with minor allele frequencies < 0.5% in public databases were considered potential candidate variants to PD. In the 18 PD patients with a positive family history that were analyzed, MLPA assays identified PRKN deletions in two patients: a homozygous exon 3–5 deletion and a heterozygous exon 4 deletion. Sixteen rare SNV were identified by NGS, four of them were novel. Seven mutations were categorized as pathogenic, five as likely pathogenic, two to be of uncertain significance, and 3 were predicted to be likely benign but may give a weaker pathogenic effect and could contribute to PD since they were found in late-onset PD patients. Rare or novel mutations that could be related to the disease were identified in 72% of these patients (13/18), including nine with bi-allelic pathogenic/likely pathogenic variants in genes causing recessive PD, particularly PRKN and PINK1 . Mutations in genes with dominant inheritance were found in 4/18 patients (22%).

Research paper thumbnail of LRRK2 impairs PINK1/Parkin-dependent mitophagy via its kinase activity: pathologic insights into Parkinson’s disease

Human Molecular Genetics

Mutations of LRRK2, encoding leucine-rich repeat kinase 2, are the leading cause of autosomal dom... more Mutations of LRRK2, encoding leucine-rich repeat kinase 2, are the leading cause of autosomal dominant Parkinson's disease (PD). The most frequent of these mutations, G2019S substitution, increases kinase activity, but it remains unclear how it causes PD. Recent studies suggest that LRRK2 modulates mitochondrial homeostasis. Mitochondrial dysfunction plays a key role in the pathogenesis of autosomal recessive PD forms linked to PARK2 and PINK1, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial kinase PINK1, which jointly regulate mitophagy. We explored the role of LRRK2 and its kinase activity in PINK1/Parkin-dependent mitophagy. LRRK2 increased mitochondrial aggregation and attenuated mitochondrial clearance in cells coexpressing Parkin and exposed to the protonophore CCCP. FRET imaging microscopy showed that LRRK2 impaired the interactions between Parkin and Drp1 and their mitochondrial targets early in mitophagy. The inhibition of LRRK2 kinase activity by a "kinase-dead" LRRK2 mutation or with a pharmacological inhibitor (LRRK2-IN-1) restored these interactions. The monitoring of mitophagy in human primary fibroblasts with the novel dual-fluorescence mtRosella reporter and a new hypothermic shock paradigm revealed similar defects in PD patients with the G2019S LRRK2 substitution or PARK2 mutations relative to healthy subjects. This defect was restored by LRRK2-IN-1 treatment in LRRK2 patients only. Our results suggest that PD forms due to LRRK2 and PARK2 mutations involve pathogenic mechanisms converging on PINK1/Parkin-dependent mitophagy.

Research paper thumbnail of Intrafamilial and interfamilial heterogeneity of PINK1-associated Parkinson's disease in Sudan

Parkinsonism & Related Disorders

Research paper thumbnail of Identification of a DAGLB Mutation in a Non‐Chinese Patient with Parkinson's Disease

Research paper thumbnail of Combination of Positional Cloning and New Generation Sequencing Identifies 3 Novel Genes in Spastic Paraplegia Involved in Common Metabolic Pathways (P01.205)

Research paper thumbnail of PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

Brain

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involve... more The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signaling 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 > 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 va...

Research paper thumbnail of ELOVL5 Mutations Cause Spinocerebellar Ataxia 38

The American Journal of Human Genetics, 2014

Research paper thumbnail of CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5

Research paper thumbnail of Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice

Research paper thumbnail of Mutations in KCND3 cause spinocerebellar ataxia type 22

Annals of Neurology, 2012

Research paper thumbnail of Alteration of Fatty-Acid-Metabolizing Enzymes Affects Mitochondrial Form and Function in Hereditary Spastic Paraplegia

The American Journal of Human Genetics, 2012

Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous groups of neurolo... more Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous groups of neurological disorders, both clinically and genetically. The disease comprises pure and complex forms that clinically include slowly progressive lower-limb spasticity resulting from degeneration of the corticospinal tract. At least 48 loci accounting for these diseases have been mapped to date, and mutations have been identified in 22 genes, most of which play a role in intracellular trafficking. Here, we identified mutations in two functionally related genes (DDHD1 and CYP2U1) in individuals with autosomal-recessive forms of HSP by using either the classical positional cloning or a combination of whole-genome linkage mapping and next-generation sequencing. Interestingly, three subjects with CYP2U1 mutations presented with a thin corpus callosum, white-matter abnormalities, and/or calcification of the basal ganglia. These genes code for two enzymes involved in fatty-acid metabolism, and we have demonstrated in human cells that the HSP pathophysiology includes alteration of mitochondrial architecture and bioenergetics with increased oxidative stress. Our combined results focus attention on lipid metabolism as a critical HSP pathway with a deleterious impact on mitochondrial bioenergetic function.

Research paper thumbnail of Clinical Variability of SYNJ1-Associated Early-Onset Parkinsonism

Frontiers in Neurology, 2021

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...

Research paper thumbnail of Genetic and Phenotypic Characterisation of Autosomal Recessive Parkinson's Disease in a Large Multicentre Cohort

SSRN Electronic Journal, 2019

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 adjus...

Research paper thumbnail of REPORT ELOVL5 Mutations Cause Spinocerebellar Ataxia 38

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative ... more Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the u3 and u6 series. Arachidoni...

Research paper thumbnail of Correction: Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Genetics in Medicine

The original version of this Article contained an error in the author name for Lionel Van Malderg... more The original version of this Article contained an error in the author name for Lionel Van Maldergem. The family name was incorrectly spelled Van Maldergen. This has now been corrected in both the PDF and HTML versions of the Article.

Research paper thumbnail of Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Genetics in Medicine

Purpose Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebel... more Purpose Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48). Methods We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance. Results STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease–like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) “second hits” in AFG3L2 , PRKCG , and TBP were detected in three families suggesting synergic effects. Conclusion Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

Research paper thumbnail of Lack of evidence for association of UQCRC1 with autosomal dominant Parkinson's disease in Caucasian families

Research paper thumbnail of Segregation of ATP10B variants in families with autosomal recessive parkinsonism

Acta Neuropathologica

Martin et al. [2] recently reported that biallelic missense and stop-gain variants in ATP10B are ... more Martin et al. [2] recently reported that biallelic missense and stop-gain variants in ATP10B are associated with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They identified double-heterozygous variants demonstrated to be located in trans in three of seven isolated cases (six with PD and one with DLB). These variants had a minor allele frequency (MAF) < 5% in the public Genome Aggregation Database (GnomAD) (https ://gnoma d.broad insti tute. org). Using cell function assays, they showed that nine of the ten variants tested resulted in ATPase activity and lipid translocation decreases and a lower level of cell protection against rotenone exposure, consistent with a loss of ATP10B function. Overall, this study indicates that biallelic ATP10B missense variants increase the risk of PD. However, the relatively high frequency of several of these ATP10B variants (> 2%), and the presence of healthy carriers homozygous for these variants in GnomAD raised questions about their pathogenicity. In a large case–control study, Real et al. [3] also questioned the implication of ATP10B variants as risk factors in the pathogenesis of PD. However, in their reply Smolders and Van Broeckhoven [4] pointed out that Real et al. [3] did not assess the phasing and therefore could not conclude that ATP10B was involved in their cohort but agreed that analyses of large number of trios are necessary to estimate the frequency of PD carriers of homozygous or compound heterozygous ATP10B variants. We assessed the presence of biallelic ATP10B variants in families with PD and their segregation with the disease, by analyzing whole-exome sequencing (WES) data from 17 PD families with autosomal recessive (AR) inheritance including at least two affected siblings (Supplementary information for patients and methods). Setting the MAF threshold at 5%, as used in Martin et al.’s paper, we identified six rare ATP10B missense variants, including three previously reported [2], in two of the 17 families. In the consanguineous Algerian FDP-167 family, the reported p.L1421F and p.I540T variants were both present in the three affected siblings, with ages at onset ranging from 30 to 35 years (Fig. 1a). Segregation analysis provided evidence for a cis location of the two variants, both inherited from the mother, who was unaffected at age 58, suggesting that they cannot be causal for PD, given the AR transmission of the disease. In the consanguineous Turkish family PD-IST-154 with typical PD (Supplementary information), the index case (IV-6) carried the p.V219M, p.G671R, and p.N865K variants in the homozygous state. The p.G671R and p.N865K variants have previously been reported to occur in cis [2]. Segregation analysis revealed that the affected sister (IV-4) carried the same variants, but in the heterozygous state, whereas the 52 year-old unaffected sister (IV-5) carried the same three variants in the homozygous state (Fig. 1b). As expected, both unaffected parents were heterozygous carriers of the three variants, whereas the father (III-1) carried another rare missense variant, p.T1019S, on the same haplotype. Segregation analysis alone is sufficient to exclude these variants as the cause of PD within this family. Moreover, we previously identified a homozygous p.L34R mutation in FBXO7 that segregated with the disease in this family (Fig. 1b) [1]. This variant is Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0040 1-020-02219 -6) contains supplementary material, which is available to authorized users.

Research paper thumbnail of Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

Frontiers in Neurology

LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (... more LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were Lesage et al. Characterization of Dominant Parkinson's Disease screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2-2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.

Research paper thumbnail of Characterization of Recessive Parkinson Disease in a Large Multicenter Study

Annals of Neurology

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

Research paper thumbnail of Gene Panel Sequencing Identifies Novel Pathogenic Mutations in Moroccan Patients with Familial Parkinson Disease

Journal of Molecular Neuroscience

In the past two decades, genetic studies of familial forms of Parkinson’s disease (PD) have shown... more In the past two decades, genetic studies of familial forms of Parkinson’s disease (PD) have shown evidence that PD has a significant genetic component. Indeed, 12 genes are strongly involved in PD causality, three of them having dominant inheritance and 9 causing early-onset autosomal recessive forms, including 3 with a typical PD and 6 with an atypical parkinsonism. The aim of this study was to determine the genetic basis of familial PD in Moroccan patients. We selected 18 Moroccan index case with familial forms of PD. Patients were first screened for exon-rearrangements by MLPA kit. They were then analyzed by gene panel next-generation sequencing (NGS). Functional variants with minor allele frequencies < 0.5% in public databases were considered potential candidate variants to PD. In the 18 PD patients with a positive family history that were analyzed, MLPA assays identified PRKN deletions in two patients: a homozygous exon 3–5 deletion and a heterozygous exon 4 deletion. Sixteen rare SNV were identified by NGS, four of them were novel. Seven mutations were categorized as pathogenic, five as likely pathogenic, two to be of uncertain significance, and 3 were predicted to be likely benign but may give a weaker pathogenic effect and could contribute to PD since they were found in late-onset PD patients. Rare or novel mutations that could be related to the disease were identified in 72% of these patients (13/18), including nine with bi-allelic pathogenic/likely pathogenic variants in genes causing recessive PD, particularly PRKN and PINK1 . Mutations in genes with dominant inheritance were found in 4/18 patients (22%).

Research paper thumbnail of LRRK2 impairs PINK1/Parkin-dependent mitophagy via its kinase activity: pathologic insights into Parkinson’s disease

Human Molecular Genetics

Mutations of LRRK2, encoding leucine-rich repeat kinase 2, are the leading cause of autosomal dom... more Mutations of LRRK2, encoding leucine-rich repeat kinase 2, are the leading cause of autosomal dominant Parkinson's disease (PD). The most frequent of these mutations, G2019S substitution, increases kinase activity, but it remains unclear how it causes PD. Recent studies suggest that LRRK2 modulates mitochondrial homeostasis. Mitochondrial dysfunction plays a key role in the pathogenesis of autosomal recessive PD forms linked to PARK2 and PINK1, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial kinase PINK1, which jointly regulate mitophagy. We explored the role of LRRK2 and its kinase activity in PINK1/Parkin-dependent mitophagy. LRRK2 increased mitochondrial aggregation and attenuated mitochondrial clearance in cells coexpressing Parkin and exposed to the protonophore CCCP. FRET imaging microscopy showed that LRRK2 impaired the interactions between Parkin and Drp1 and their mitochondrial targets early in mitophagy. The inhibition of LRRK2 kinase activity by a "kinase-dead" LRRK2 mutation or with a pharmacological inhibitor (LRRK2-IN-1) restored these interactions. The monitoring of mitophagy in human primary fibroblasts with the novel dual-fluorescence mtRosella reporter and a new hypothermic shock paradigm revealed similar defects in PD patients with the G2019S LRRK2 substitution or PARK2 mutations relative to healthy subjects. This defect was restored by LRRK2-IN-1 treatment in LRRK2 patients only. Our results suggest that PD forms due to LRRK2 and PARK2 mutations involve pathogenic mechanisms converging on PINK1/Parkin-dependent mitophagy.