Publications by authors named "Emeline Mundwiller"

22 Publications

  • Page 1 of 1

A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.

Am J Hum Genet 2015 Nov 8;97(5):726-37. Epub 2015 Oct 8.

INSERM U 1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, 75013 Paris, France; Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Ecole Pratique des Hautes Etudes, 75014 Paris, France; Centre de Référence de Neurogénétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France. Electronic address:

Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. In a large family affected by ADCA and mild pyramidal signs, we searched for the causative variant by combining linkage analysis and whole-exome sequencing. In CACNA1G, we identified a c.5144G>A mutation, causing an arginine-to-histidine (p.Arg1715His) change in the voltage sensor S4 segment of the T-type channel protein Cav3.1. Two out of 479 index subjects screened subsequently harbored the same mutation. We performed electrophysiological experiments in HEK293T cells to compare the properties of the p.Arg1715His and wild-type Cav3.1 channels. The current-voltage and the steady-state activation curves of the p.Arg1715His channel were shifted positively, whereas the inactivation curve had a higher slope factor. Computer modeling in deep cerebellar nuclei (DCN) neurons suggested that the mutation results in decreased neuronal excitability. Taken together, these data establish CACNA1G, which is highly expressed in the cerebellum, as a gene whose mutations can cause ADCA. This is consistent with the neuropathological examination, which showed severe Purkinje cell loss. Our study further extends our knowledge of the link between calcium channelopathies and CAs.
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http://dx.doi.org/10.1016/j.ajhg.2015.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667105PMC
November 2015

CIC inactivating mutations identify aggressive subset of 1p19q codeleted gliomas.

Ann Neurol 2015 Sep 27;78(3):355-74. Epub 2015 Jul 27.

Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France.

Objective: CIC gene is frequently mutated in oligodendroglial tumors with 1p19q codeletion. However, clinical and biological impact remain poorly understood.

Methods: We sequenced the CIC gene on 127 oligodendroglial tumors (109 with the 1p19q codeletion) and analyzed patients' outcome. We compared magnetic resonance imaging, transcriptomic profile, and CIC protein expression of CIC wild-type (WT) and mutant gliomas. We compared the level of expression of CIC target genes on Hs683-IDH1(R132H) cells transfected with lentivirus encoding mutant and WT CIC.

Results: We found 63 mutations affecting 60 of 127 patients, virtually all 1p19q codeleted and IDH mutated (59 of 60). In the 1p19q codeleted gliomas, CIC mutations were associated with a poorer outcome by uni- (p = 0.001) and multivariate analysis (p < 0.016). CIC mutation prognostic impact was validated on the TCGA cohort. CIC mutant grade II codeleted gliomas spontaneously grew faster than WTs. Transcriptomic analysis revealed an enrichment of proliferative pathways and oligodendrocyte precursor cell gene expression profile in CIC mutant gliomas, with upregulation of normally CIC repressed genes ETV1, ETV4, ETV5, and CCND1. Various missense mutations resulted in CIC protein expression loss. Moreover, a truncating CIC mutation resulted in a defect of nuclear targeting of CIC protein to the nucleus in a human glioma cell line expressing IDH1(R132H) and overexpression of CCND1 and other new target genes of CIC, such as DUSP4 and SPRED1.

Interpretation: CIC mutations result in protein inactivation with upregulation of CIC target genes, activation of proliferative pathways, inhibition of differentiation, and poorer outcome in patients with a 1p19q codeleted glioma.
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http://dx.doi.org/10.1002/ana.24443DOI Listing
September 2015

GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia.

Neurology 2015 Apr 3;84(17):1751-9. Epub 2015 Apr 3.

From Institut du Cerveau et de la Moelle épinière (M.C., A.B., G.S., A.D.), ICM, Paris; CNRS (M.C., A.B., G.S., A.D.), UMR 7225, Paris; Sorbonne Universités (M.C., A.B., G.S., A.D.), UPMC Univ Paris 06, UMRS_1127, Paris; INSERM (M.C., E.M., A.B., G.S., A.D.), U 1127, Paris, France; Laboratory of Human Molecular Genetics (M.C.), de Duve Institute, Université catholique de Louvain, Brussels, Belgium; Laboratoire de Neurogénétique (M.C., G.S.), Ecole Pratique des Hautes Etudes, ICM, GHU Pitié-Salpêtrière, Paris; Centre de Référence Malformations et Maladies Congénitales du Cervelet (L.B., D.R., S.C.-B., C.R., A.A.), Paris-Lyon-Lille; INSERM U1141 (L.B., D.R.), Paris; APHP (L.B., S.C.-B.), Armand-Trousseau Hospital, Department of Genetics, Paris, France; Service de Neurologie (M.A.-B.), CHU Bab el Oued, Alger, Algeria; APHP (D.R., A.A.), Armand-Trousseau Hospital, Department of Neuropediatrics, UPMC Univ Paris 06; Hospices Civils de Lyon (C.R.), HFME, Service de Neuropédiatrie, Bron; Centre Hospitalier du Pays d'Aix (M.-A.C.), Service de Pédiatrie, Aix en Provence; APHM (M.M.), Service de neurologie pédiatrique, Hôpital de la Timone, Marseille; Service de Génétique (A.T.), Hôpital Bretonneau, Centre Hospitalier Universitaire, Tours; Centre National de Génotypage (D.B., V.M., J.-F.D.), Institut de Génomique, CEA, Evry; APHP (A.B., D.H., A.D.), Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié-Salpêtrière, Paris; Centre de Référence Déficiences Intellectuelles de causes rares (D.H.), Paris; and Groupe de Recherche Clinique déficiences intellectuelles (D.H.), UPMC Univ Paris 06, France.

Objectives: In a large family of Algerian origin, we aimed to identify the genetic mutation segregating with simultaneous presence of adult-onset, paucisymptomatic, slowly progressive, cerebellar ataxia in 7 adults and congenital ataxia in 1 child, and then to assess the involvement of GRID2 mutations in 144 patients with congenital cerebellar ataxia.

Methods: We used a combined approach of linkage analysis and whole-exome sequencing in one family, and a targeted gene panel sequencing approach in 144 congenital ataxias.

Results: In the large family with spinocerebellar ataxia, we identified a missense mutation (c.1966C>G/p.Leu656Val) in the GRID2 gene, in a heterozygous state in adults, and in a homozygous state in one child with congenital ataxia, compatible with a semidominant transmission pattern. In 144 patients affected with congenital ataxia, we identified 2 missense de novo GRID2 mutations in 2 children (c.1960G>A/p.Ala654Thr, c.1961C>A/p.Ala654Asp). They affect the same amino acid as the previously described Lurcher mutation in mice; the variant in the large family concerns a nearby amino acid.

Conclusions: In humans, GRID2 had only been involved in ataxia through complete loss-of-function mutations due to exon deletions. We report the first point mutations in this gene, with putative gain-of-function mechanisms, and a semidominant transmission as was observed in the Lurcher mice model. Of note, cerebellar ataxia is the core phenotype, but with variable severity ranging from very mild adult-onset to congenital-onset ataxias linked to both the heterozygous and homozygous state of the variant, and the position of the mutation.
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http://dx.doi.org/10.1212/WNL.0000000000001524DOI Listing
April 2015

The impact of rare variants in FUS in essential tremor.

Mov Disord 2015 Apr 28;30(5):721-4. Epub 2015 Jan 28.

Department of Neurology, University Hospital Schleswig Holstein, Kiel, Germany.

Objective: We analyzed the coding region of the Fused in Sarcoma (FUS) gene in familial essential tremor (ET) and reviewed previous studies assessing FUS variants in ET.

Background: ET is often a familial disorder with an autosomal dominant inheritance pattern. A potentially causative variant in FUS has been identified in one ET family. Subsequent studies described further putatively causal variants.

Methods: We performed DNA sequencing of FUS in 85 unrelated, familial German and French definite ET patients.

Results: We did not find novel variants affecting the protein sequence. Seven previously published studies and data from the exome variant server (EVS) showed that rare exonic variants in FUS are not more frequent in ET than in the general population.

Conclusions: Our findings provide no evidence for a role of rare genetic variants in the pathogenesis of ET, apart from the initially published FUS mutation segregating in a large ET family.
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http://dx.doi.org/10.1002/mds.26145DOI Listing
April 2015

Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia.

Neurology 2015 Feb 21;84(7):659-67. Epub 2015 Jan 21.

From the Department of Neurology and Agnes Ginges Center for Human Neurogenetics (A.L., P.P.), Department of Genetics and Metabolic Diseases (B.-E.Z., M.A., L.C., R.S., I.L., V.M.), Neuro-Ophthalmology Center, Department of Ophthalmology (S.D.), and Department of Radiology (J.M.G.), Hebrew University-Hadassah Medical Center, Jerusalem, Israel; Institut für Zytobiologie und Zytopathologie (C.S., R.L.), Philipps-Universität Marburg, Germany; Laboratoire de Neurogénétique (G.S., M.G.), Ecole Pratique des Hautes Etudes-heSam Universite, Institut du Cerveau et de la Moelle épinière, Paris; Inserm U1127 (G.S., M.G., E.M., A.B.), CNRS UMR7225, Sorbonne Universites, UPMC Univ Paris 06 UMR_1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris; APHP (G.S., A.B.), Fédération de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris; Institut du Cerveau et de la Moelle épinière (G.S., E.M., A.B.), Genotyping and Sequencing Facility, Paris, France; Department of Neurology (A.M.), Shaare Zedek Medical Center, Jerusalem, Israel; Max-Planck-Institut für terrestrische Mikrobiologie (R.L.), Marburg; and LOEWE Zentrum für Synthetische Mikrobiologie SynMikro (R.L.), Marburg, Germany.

Objective: To present the clinical, molecular, and cell biological findings in a family with an autosomal recessive form of hereditary spastic paraplegia characterized by a combination of spastic paraplegia, optic atrophy, and peripheral neuropathy (SPOAN).

Methods: We used a combination of whole-genome linkage analysis and exome sequencing to map the disease locus and to identify the responsible gene. To analyze the physiologic consequences of the disease, we used biochemical and cell biological methods.

Results: Ten members of a highly consanguineous family manifested a childhood-onset SPOAN-like phenotype with slow progression into late adulthood. We mapped this disorder to a locus on chromosome 1q and identified a homozygous donor splice-site mutation in the IBA57 gene, previously implicated in 2 infants with lethal perinatal encephalomyopathy. This gene encodes the mitochondrial iron-sulfur (Fe/S) protein assembly factor IBA57. In addition to a severely decreased amount of normal IBA57 messenger RNA, a patient's cells expressed an aberrantly spliced messenger RNA with a premature stop codon. Lymphoblasts contained 10-fold-lower levels of wild-type, but no signs of truncated IBA57 protein. The decrease in functional IBA57 resulted in reduced levels and activities of several mitochondrial [4Fe-4S] proteins, including complexes I and II, while mitochondrial [2Fe-2S] proteins remained normal.

Conclusions: Our findings reinforce the suggested specific function of IBA57 in mitochondrial [4Fe-4S] protein maturation and provide additional evidence for its role in human disease. The less decreased IBA57 protein level in this family explains phenotypic differences compared with the previously described lethal encephalomyopathy with no functional IBA57.
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http://dx.doi.org/10.1212/WNL.0000000000001270DOI Listing
February 2015

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders.

Neurology 2014 Sep 6;83(11):990-5. Epub 2014 Aug 6.

From the Institut du Cerveau et de la Moelle épinière (ICM) (S.L., S.M., G.S., S.R.-P., C.M., A.C., S.D., E.M., P.C., A.B., I.L., E.K.), Sorbonne Université, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, F-75013, Paris; Ecole Pratique des Hautes Etudes, Laboratoire de Neurogénétique, ICM (G.S.), HéSam Université, GHU Pitié-Salpêtrière, F-75013, Paris; Fédération des Maladies du Système Nerveux, Centre de référence maladies rares SLA (F.S., V.M.), Département de Neuropathologie (D.S.), Department of Neurology (A.-M.B.), Unité Fonctionnelle de neurogénétique moléculaire et cellulaire (E.L.), Département de Génétique et Cytogénétique (A.B.), and Centre de référence Démences Rares (I.L.), AP-HP, Hôpital Pitié-Salpêtrière, F-75013, Paris; Inserm U1079 (D.H.), Rouen; Centre mémoire (F.P.), Université Lille Nord de France, EA1046, CHU, Lille; Neuroépidémiologie Tropicale (P.C.), Université de Limoges INSERM UMR1094, Limoges; Service de Neurologie et Pathologie du Mouvement (V.D.-B.), Hôpital Roger Salengro, CHRU Lille; and Service de neurologie (C.T.), Hôpital de Hautepierre, CHU de Strasbourg, 1 Avenue Molière, Strasbourg, France.

Objective: The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion.

Methods: We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS).

Results: We found a significant association with intermediate repeat size (≥29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls.

Conclusions: ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS. Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS.
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http://dx.doi.org/10.1212/WNL.0000000000000778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162303PMC
September 2014

DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy.

Neurology 2014 Jun 9;82(23):2101-6. Epub 2014 May 9.

From the Department of Neurology (F.P.), and Service of Genetic Medicine (S.E.A.), University Hospitals of Geneva; Department of Genetic Medicine and Development (P.M.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.), University of Geneva, Switzerland; Institut national de la santé et de la recherche médicale (INSERM) (V.N., S.I., C.D., I.A.-G., M.V., M.B., E.L., S.B.), U1127, ICM, Paris, F-75013 Paris; Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013 Paris (V.N., S.I., C.D., I.A.-G., M.V., M.B., E.L., S.B.), Paris; CNRS (V.N., S.I., C.D., I.A.-G., M.V., M.B., E.L., S.B.), UMR7225, Hôpital de la Pitié-Salpêtrière, Paris; Epilepsy Unit (V.N., I.A.-G., M.V., M.B.), ICM, Paris, F-75013 Paris, France (V.N., S.I., C.D., I.A.-G., M.V., M.B., E.L., S.B.), and Département de Génétique et de Cytogénétique (C.D., E.L.), AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris; Epilepsy, Sleep and Pediatric Neurophysiology (J.d.B.), University Hospitals of Lyon; Hospices Civils de Lyon (D.V.), HFME, centre de référence déficiences intellectuelles de causes rares et sclérose tubéreuse de Bourneville, Bron, France; Neurogenetics Group (S.W., A.S., P.D.J.), Department of Molecular Genetics, VIB, Antwerp; Laboratory of Neurogenetics (S.W., A.S., P.D.J.), Institute Born-Bunge, University of Antwerp, Belgium; Epilepsy Centre Kempenhaeghe (S.W.), Oosterhout, the Netherlands; Algemeen Stedelijk Ziekenhuis (E.F.), Aalst; Division of Neurology (P.D.J.), Antwerp University Hospital, Antwerp University, Belgium; Centre hospitalier général de Valence (M.V.R.); Department of Medical Genetics (G.L.), Hospices Civils de Lyon; Claude Bernard Lyon I University (G.L.); CRNL (G.L.), CNRS UMR 5292, INSERM U1028, Lyon; Centre de référence épilepsies rares et Sclérose tubéreuse de Bourneville (I.A.-G., M.B.); Genotyping and Sequencing Platform, ICM (E.M.), and DNA and Cell Bank (P.C.), Hôpital Pitié-Salpêtrière, Paris, France; Department of Surge

Objective: To study the prevalence of DEPDC5 mutations in a series of 30 small European families with a phenotype compatible with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).

Methods: Thirty unrelated families referred with ADNFLE were recruited in France, Italy, Germany, Belgium, and Norway. Whole-exome sequencing was performed in 10 probands and direct sequencing of the DEPDC5 coding sequence in 20 probands. Testing for nonsense-mediated messenger RNA decay (NMD) was performed in lymphoblastic cells.

Results: Exome sequencing revealed a splice acceptor mutation (c.2355-2A>G) in DEPDC5 in the proband of a German family. In addition, 3 nonsense DEPDC5 mutations (p.Arg487*, p.Arg1087*, and p.Trp1369*) were detected in the probands of 2 French and one Belgian family. The nonsense mutations p.Arg487* and p.Arg1087* were targeted by NMD, leading to the degradation of the mutated transcripts. At the clinical level, 78% of the patients with DEPDC5 mutations were drug resistant.

Conclusions: DEPDC5 loss-of-function mutations were found in 13% of the families with a presentation of ADNFLE. The rate of drug resistance was high in patients with DEPDC5 mutations. Small ADNFLE pedigrees with DEPDC5 mutations might actually represent a part of the broader familial focal epilepsy with variable foci phenotype.
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http://dx.doi.org/10.1212/WNL.0000000000000488DOI Listing
June 2014

TP53 and p53 statuses and their clinical impact in diffuse low grade gliomas.

J Neurooncol 2014 May 4;118(1):131-9. Epub 2014 Mar 4.

Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), Université Pierre et Marie Curie-Paris 6, UMRS 975, Paris, France.

TP53 is a pivotal gene frequently mutated in diffuse gliomas and particularly in astrocytic tumors. The majority of studies dedicated to TP53 in gliomas were focused on mutational hotspots located in exons 5-8. Recent studies have suggested that TP53 is also mutated outside the classic mutational hotspots reported in gliomas. Therefore, we have sequenced all TP53 coding exons in a retrospective series of 61 low grade gliomas (LGG) using high throughput sequencing technology. In addition, TP53 mutational status was correlated with: (i) p53 expression, (ii) tumor type, (iii) chromosome arms 1p/19q status and (iv) clinical features of patients. The cohort included 32 oligodendrogliomas (O), 21 oligoastrocytomas (M) and 8 astrocytomas (A). TP53 mutation was detected in 52.4% (32/61) of tumors (34% of O, 71.4% of M and 75% of A). All mutations (38 mutations in 32 samples) were detected in exons 4, 5, 6, 7, 8 and 10. Missense and non-missense mutations, including seven novel mutations, were detected in 42.6 and 9.8% of tumors respectively. TP53 mutations were almost mutually exclusive with 1p/19q co-deletion and were associated with: (i) astrocytic phenotype, (ii) younger age, (iii) p53 expression. Using a threshold of 10% p53-positive tumor cells, p53 expression is an interesting surrogate marker for missense TP53 mutations (Se = 92%; Sp = 79.4%) but not for non-missense mutation (18.4% of mutations). TP53 and p53 statuses were not prognostic in LGG. In conclusion, we have identified novel TP53 mutations in LGG. TP53 mutations outside exons 4-8 are rare. Although it remains imperfect, p53 expression with a threshold of 10% is a good surrogate marker for missense TP53 mutations and appears helpful in the setting of LGG phenotype diagnosis.
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http://dx.doi.org/10.1007/s11060-014-1407-4DOI Listing
May 2014

Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia.

Am J Hum Genet 2014 Feb 2;94(2):268-77. Epub 2014 Jan 2.

Université Pierre and Marie Curie - Paris VI, Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 975, 75013 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, 75013 Paris, France. Electronic address:

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurological conditions. Their main pathogenic mechanisms are thought to involve alterations in endomembrane trafficking, mitochondrial function, and lipid metabolism. With a combination of whole-genome mapping and exome sequencing, we identified three mutations in REEP2 in two families with HSP: a missense variant (c.107T>A [p.Val36Glu]) that segregated in the heterozygous state in a family with autosomal-dominant inheritance and a missense change (c.215T>A [p.Phe72Tyr]) that segregated in trans with a splice site mutation (c.105+3G>T) in a family with autosomal-recessive transmission. REEP2 belongs to a family of proteins that shape the endoplasmic reticulum, an organelle that was altered in fibroblasts from an affected subject. In vitro, the p.Val36Glu variant in the autosomal-dominant family had a dominant-negative effect; it inhibited the normal binding of wild-type REEP2 to membranes. The missense substitution p.Phe72Tyr, in the recessive family, decreased the affinity of the mutant protein for membranes that, together with the splice site mutation, is expected to cause complete loss of REEP2 function. Our findings illustrate how dominant and recessive inheritance can be explained by the effects and nature of mutations in the same gene. They have also important implications for genetic diagnosis and counseling in clinical practice because of the association of various modes of inheritance to this new clinico-genetic entity.
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http://dx.doi.org/10.1016/j.ajhg.2013.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928657PMC
February 2014

New findings in a global approach to dissect the whole phenotype of PLA2G6 gene mutations.

PLoS One 2013 9;8(10):e76831. Epub 2013 Oct 9.

Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076831PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792983PMC
June 2014

Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia.

Am J Hum Genet 2013 Jul 6;93(1):118-23. Epub 2013 Jun 6.

Service de Neurologie, Hôpital Universitaire Habib Bourguiba, 3029 Sfax, Tunisia.

Hereditary spastic paraplegias (HSPs) form a heterogeneous group of neurological disorders. A whole-genome linkage mapping effort was made with three HSP-affected families from Spain, Portugal, and Tunisia and it allowed us to reduce the SPG26 locus interval from 34 to 9 Mb. Subsequently, a targeted capture was made to sequence the entire exome of affected individuals from these three families, as well as from two additional autosomal-recessive HSP-affected families of German and Brazilian origins. Five homozygous truncating (n = 3) and missense (n = 2) mutations were identified in B4GALNT1. After this finding, we analyzed the entire coding region of this gene in 65 additional cases, and three mutations were identified in two subjects. All mutated cases presented an early-onset spastic paraplegia, with frequent intellectual disability, cerebellar ataxia, and peripheral neuropathy as well as cortical atrophy and white matter hyperintensities on brain imaging. B4GALNT1 encodes β-1,4-N-acetyl-galactosaminyl transferase 1 (B4GALNT1), involved in ganglioside biosynthesis. These findings confirm the increasing interest of lipid metabolism in HSPs. Interestingly, although the catabolism of gangliosides is implicated in a variety of neurological diseases, SPG26 is only the second human disease involving defects of their biosynthesis.
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http://dx.doi.org/10.1016/j.ajhg.2013.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710753PMC
July 2013

Mutations of DEPDC5 cause autosomal dominant focal epilepsies.

Nat Genet 2013 May 31;45(5):552-5. Epub 2013 Mar 31.

Institut National de la Santé et de la Recherche Médicale (INSERM) U975, Institut du Cerveau et de la Moelle Epinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France.

The main familial focal epilepsies are autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy and familial focal epilepsy with variable foci. A frameshift mutation in the DEPDC5 gene (encoding DEP domain-containing protein 5) was identified in a family with focal epilepsy with variable foci by linkage analysis and exome sequencing. Subsequent pyrosequencing of DEPDC5 in a cohort of 15 additional families with focal epilepsies identified 4 nonsense mutations and 1 missense mutation. Our findings provided evidence of frequent (37%) loss-of-function mutations in DEPDC5 associated with a broad spectrum of focal epilepsies. The implication of a DEP (Dishevelled, Egl-10 and Pleckstrin) domain-containing protein that may be involved in membrane trafficking and/or G protein signaling opens new avenues for research.
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http://dx.doi.org/10.1038/ng.2601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010101PMC
May 2013

Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia.

Am J Hum Genet 2013 Feb 17;92(2):238-44. Epub 2013 Jan 17.

Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Pitie-Salpêtrière Hospital, Université Pierre et Marie Curie (Paris 6), Paris, France.

Spastic paraplegia 46 refers to a locus mapped to chromosome 9 that accounts for a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP). With next-generation sequencing in three independent families, we identified four different mutations in GBA2 (three truncating variants and one missense variant), which were found to cosegregate with the disease and were absent in controls. GBA2 encodes a microsomal nonlysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide to free glucose and ceramide and the hydrolysis of bile acid 3-O-glucosides. The missense variant was also found at the homozygous state in a simplex subject in whom no residual glucocerebrosidase activity of GBA2 could be evidenced in blood cells, opening the way to a possible measurement of this enzyme activity in clinical practice. The overall phenotype was a complex HSP with mental impairment, cataract, and hypogonadism in males associated with various degrees of corpus callosum and cerebellar atrophy on brain imaging. Antisense morpholino oligonucleotides targeting the zebrafish GBA2 orthologous gene led to abnormal motor behavior and axonal shortening/branching of motoneurons that were rescued by the human wild-type mRNA but not by applying the same mRNA containing the missense mutation. This study highlights the role of ceramide metabolism in HSP pathology.
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http://dx.doi.org/10.1016/j.ajhg.2012.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567271PMC
February 2013

Mutations in KCND3 cause spinocerebellar ataxia type 22.

Ann Neurol 2012 Dec;72(6):859-69

Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan.

Objective: To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23.

Methods: We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions.

Results: We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame 3-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K(+) channel conductance in whole cell patch-clamp recordings.

Interpretation: Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration.
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http://dx.doi.org/10.1002/ana.23701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085146PMC
December 2012

KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.

Eur J Hum Genet 2012 Jun 18;20(6):645-9. Epub 2012 Jan 18.

INSERM, U975, Paris, France.

The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotype-genotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa.
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http://dx.doi.org/10.1038/ejhg.2011.261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355258PMC
June 2012

REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.

Hum Mutat 2011 Oct 9;32(10):1118-27. Epub 2011 Sep 9.

Université Bordeaux Segalen, Laboratoire Maladies Rares: Génétique et Métabolisme, Bordeaux, France.

Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized at least by slowly progressive spasticity of the lower limbs. Mutations in REEP1 were recently associated with a pure dominant HSP, SPG31. We sequenced all exons of REEP1 and searched for rearrangements by multiplex ligation-dependent probe amplification (MLPA) in a large panel of 175 unrelated HSP index patients from kindreds with dominant inheritance (AD-HSP), with either pure (n = 102) or complicated (n = 73) forms of the disease, after exclusion of other known HSP genes. We identified 12 different heterozygous mutations, including two exon deletions, associated with either a pure or a complex phenotype. The overall mutation rate in our clinically heterogeneous sample was 4.5% in French families with AD-HSP. The phenotype was restricted to pyramidal signs in the lower limbs in most patients but nine had a complex phenotype associating axonal peripheral neuropathy (= 5/11 patients) including a Silver-like syndrome in one patient, and less frequently cerebellar ataxia, tremor, dementia. Interestingly, we evidenced abnormal mitochondrial network organization in fibroblasts of one patient in addition to defective mitochondrial energy production in both fibroblasts and muscle, but whether these anomalies are directly or indirectly related to the mutations remains uncertain.
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http://dx.doi.org/10.1002/humu.21542DOI Listing
October 2011

Kjellin syndrome: long-term neuro-ophthalmologic follow-up and novel mutations in the SPG11 gene.

Ophthalmology 2011 Mar 29;118(3):564-73. Epub 2010 Oct 29.

Service d'Exploration de la Vision et Neuro-Ophtalmologie, Hôpital Roger-Salengro, CHRU de Lille, Lille Cedex, France.

Objective: Kjellin's syndrome is a hereditary neuro-ophthalmologic syndrome. We describe the clinical phenotypes of 7 patients, identifying the responsible mutations for 4 of them. A 10-year ophthalmologic and neurologic follow-up of 5 patients allowed us to describe the disease's characteristics, early symptoms and progression, associated ocular signs, and retinal changes in carriers.

Design: Retrospective clinical study and molecular genetics investigation.

Participants: The records of 7 patients with Kjellin's syndrome were analyzed retrospectively.

Methods: All patients underwent full neurologic and ophthalmologic examinations. The neurologic examinations included assessments of initial symptoms, intelligence quotient tests, psychologic tests, and either magnetic resonance imaging or computed tomography. The ophthalmologic examinations included visual acuity on an Early Treatment Diabetic Retinopathy Study chart, intraocular pressure color vision assessment, slit-lamp and fundus examination, Goldmann perimetry, fundus autofluorescence, optical coherence tomography and fluorescein angiography, electro-oculography, electroretinography, and flash visual evoked potentials. Direct sequencing of the SPG11 and SPG15 genes and gene-dosage analysis for the former were performed for 4 of these index patients.

Main Outcome Measures: Identification of new mutations in the SPG11 gene, validating its implication in Kjellin's syndrome.

Results: The first signs appear before the age of 10 years, with late verbal development and difficulty running and walking. Life expectancy is between 30 and 40 years. The secondary ophthalmologic symptoms only moderately affect visual acuity. In addition to the classic symptoms, 3 of the 7 patients displayed small whitish lens opacities, and 3 neurologically unaffected parents (father or mother), all heterozygous carriers, exhibited whitish retinal dots. All the patients who were tested carried SPG11, not SPG15, mutations.

Conclusions: Neurologic signs of SPG11 mutations emerge in early infancy, with walking and language difficulties. Onset of paraplegia occurs at the end of the first decade or during the second decade. Retinal changes, an integral part of SPG11 mutations in this series of patients, are only observed once the paraplegia has become apparent.
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http://dx.doi.org/10.1016/j.ophtha.2010.07.024DOI Listing
March 2011

Spinocerebellar ataxia type 11 (SCA11) is an uncommon cause of dominant ataxia among French and German kindreds.

J Neurol Neurosurg Psychiatry 2010 Nov 28;81(11):1229-32. Epub 2010 Jul 28.

Department of Medical Genetics, University of Tübingen, Tübingen, Germany.

Background: At least 28 loci have been linked to autosomal dominant spinocerebellar ataxia (ADCA). Causative genes have been cloned for 10 nucleotide repeat expansions (SCA1, 2, 3, 6, 7, 8, 10, 12, 17 and 31) and six genes with classical mutations (SCA5, 13, 14, 15/16, 27 and 28). Recently, a large British pedigree linked to SCA11 has been reported to carry a mutation in the TTBK2 gene. In order to assess the prevalence and phenotypic spectrum of SCA11, the authors screened 148 index patients of predominantly German (n=69) and French (n=79) descent with ADCA tested negative for a panel of SCA mutations (SCA1, 2, 3, 6, 7 and 17), for mutations in TTBK2.

Methods: In the German ADCA cohort, the complete coding sequence of the TTBK2 gene was PCR-amplified and screened for mutations by high-resolution-melting (HRM) analysis. In the French cohort, exons known to carry mutations were directly sequenced. For both cohorts, the gene-dosage alterations were assessed using a customised multiplex ligation probe amplification (MLPA) assay.

Results: In two of 148 ADCA families--one German and one French--the authors identified a potentially disease-causing SCA11 mutation. Interestingly, both carried an identical two-basepair deletion (c.1306_1307delGA, p.D435fs448X in exon 12) leading to a premature stop codon. Gene-dosage alterations were not detected in the TTBK2 gene. Clinically, the SCA11 patients had phenotypic characteristics as described before presenting with slowly progressive almost pure cerebellar ataxia with normal life expectancy.

Conclusion: SCA11 presented as ADCA III according to Harding's classification and is a rare cause of spinocerebellar ataxia in Caucasians accounting for less than 1% of dominant ataxias in central Europe.
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http://dx.doi.org/10.1136/jnnp.2009.202150DOI Listing
November 2010

A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia.

PLoS Biol 2010 Jun 29;8(6):e1000408. Epub 2010 Jun 29.

Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany.

DNA repair is essential to maintain genome integrity, and genes with roles in DNA repair are frequently mutated in a variety of human diseases. Repair via homologous recombination typically restores the original DNA sequence without introducing mutations, and a number of genes that are required for homologous recombination DNA double-strand break repair (HR-DSBR) have been identified. However, a systematic analysis of this important DNA repair pathway in mammalian cells has not been reported. Here, we describe a genome-scale endoribonuclease-prepared short interfering RNA (esiRNA) screen for genes involved in DNA double strand break repair. We report 61 genes that influenced the frequency of HR-DSBR and characterize in detail one of the genes that decreased the frequency of HR-DSBR. We show that the gene KIAA0415 encodes a putative helicase that interacts with SPG11 and SPG15, two proteins mutated in hereditary spastic paraplegia (HSP). We identify mutations in HSP patients, discovering KIAA0415/SPG48 as a novel HSP-associated gene, and show that a KIAA0415/SPG48 mutant cell line is more sensitive to DNA damaging drugs. We present the first genome-scale survey of HR-DSBR in mammalian cells providing a dataset that should accelerate the discovery of novel genes with roles in DNA repair and associated medical conditions. The discovery that proteins forming a novel protein complex are required for efficient HR-DSBR and are mutated in patients suffering from HSP suggests a link between HSP and DNA repair.
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http://dx.doi.org/10.1371/journal.pbio.1000408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893954PMC
June 2010

A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum.

Neurogenetics 2010 Oct 1;11(4):441-8. Epub 2010 Jul 1.

Department of Neurology, Habib Bourguiba University Hospital, Sfax, Tunisia.

Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) and mental impairment is a frequent subtype of complicated HSP, often inherited as an autosomal recessive (AR) trait. It is clear from molecular genetic analyses that there are several underlying causes of this syndrome, with at least six genetic loci identified to date. However, SPG11 and SPG15 are the two major genes for this entity. To map the responsible gene in a large AR-HSP-TCC family of Tunisian origin, we investigated a consanguineous family with a diagnosis of AR-HSP-TCC excluded for linkage to the SPG7, SPG11, SPG15, SPG18, SPG21, and SPG32 loci. A genome-wide scan was undertaken using 6,090 SNP markers covering all chromosomes. The phenotypic presentation in five patients was suggestive of a complex HSP that associated an early-onset spastic paraplegia with mild handicap, mental deterioration, congenital cataract, cerebellar signs, and TCC. The genome-wide search identified a single candidate region on chromosome 9, exceeding the LOD score threshold of +3. Fine mapping using additional markers narrowed the candidate region to a 45.1-Mb interval (15.4 cM). Mutations in three candidate genes were excluded. The mapping of a novel AR-HSP-TCC locus further demonstrates the extensive genetic heterogeneity of this condition. We propose that testing for this locus should be performed, after exclusion of mutations in SPG11 and SPG15 genes, in AR-HSP-TCC families, especially when cerebellar ataxia and cataract are present.
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http://dx.doi.org/10.1007/s10048-010-0249-2DOI Listing
October 2010

Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10.

Hum Mutat 2009 Feb;30(2):E376-85

INSERM, UMR_S679, Paris, France.

Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. Only a few different mutations in the SPG10 gene, KIF5A, have been described in pure dominant forms of the disease. We sequenced the motor domain of KIF5A in a large panel of 205 European HSP patients with either pure or complicated forms of the disease. We identified eight different heterozygous missense mutations, seven novels, in eight different families of French origin. Residue R280 was a mutational hot spot. Interestingly, the patients in 7/8 families had a complex phenotype, with peripheral neuropathy, severe upper limb amyotrophy (Silver syndrome-like), mental impairment, parkinsonism, deafness and/or retinitis pigmentosa as variably associated features. We report the largest series of SPG10 families described so far, which extends both the mutational spectrum of the disease and its phenotype, which now includes complicated forms of HSP. SPG10 mutations were found in 10% of our complicated forms of HSP, suggesting that mutations in KIF5A represent the major cause of complicated AD-HSP in France.
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http://dx.doi.org/10.1002/humu.20920DOI Listing
February 2009