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June 2015; 1 (1) Clinical/Scientific NotesOpen Access

Loss-of-function mutations in RAB39B are associated with typical early-onset Parkinson disease

Suzanne Lesage, Jose Bras, Florence Cormier-Dequaire, Christel Condroyer, Aude Nicolas, Lee Darwent, Rita Guerreiro, Elisa Majounie, Monica Federoff, Peter Heutink, Nicholas W. Wood, Thomas Gasser, John Hardy, François Tison, Andrew Singleton, Alexis Brice, For the French Parkinson's Disease Genetics Study Group (PDG) and the International Parkinson's Disease Genomics Consortium (IPDGC)
First published June 18, 2015, DOI: https://doi.org/10.1212/NXG.0000000000000009
Suzanne Lesage
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Jose Bras
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Florence Cormier-Dequaire
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Christel Condroyer
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Aude Nicolas
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Lee Darwent
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Rita Guerreiro
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Elisa Majounie
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Monica Federoff
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Peter Heutink
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Nicholas W. Wood
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Thomas Gasser
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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John Hardy
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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François Tison
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Andrew Singleton
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Alexis Brice
From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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From the Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.
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Loss-of-function mutations in RAB39B are associated with typical early-onset Parkinson disease
Suzanne Lesage, Jose Bras, Florence Cormier-Dequaire, Christel Condroyer, Aude Nicolas, Lee Darwent, Rita Guerreiro, Elisa Majounie, Monica Federoff, Peter Heutink, Nicholas W. Wood, Thomas Gasser, John Hardy, François Tison, Andrew Singleton, Alexis Brice, For the French Parkinson's Disease Genetics Study Group (PDG) and the International Parkinson's Disease Genomics Consortium (IPDGC)
Neurol Genet Jun 2015, 1 (1) e9; DOI: 10.1212/NXG.0000000000000009

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Rab proteins are small molecular weight guanosine triphosphatases involved in the regulation of vesicular trafficking.1 Three of 4 X-linked RAB genes are specific to the brain, including RAB39B. Recently, Wilson et al.2 reported that mutations in RAB39B cause X-linked intellectual disability (ID) and pathologically confirmed Parkinson disease (PD). They identified a ∼45-kb deletion resulting in the complete loss of RAB39B in an Australian kindred and a missense mutation in a large Wisconsin kindred. Here, we report an additional affected man with typical PD and mild mental retardation harboring a new truncating mutation in RAB39B.

Methods.

We looked for coding and splice site mutations in RAB39B (RefSeq accession number NM_171998.2) using data mining in exomes from a cohort of 1,348 unrelated patients with PD (60% men, mean age at onset 41.7 ± 11.0 years) and 530 controls (65% men, mean age at examination 45.1 ± 10.7 years), mostly of European ancestry, recruited through the International Parkinson's Disease Genomics Consortium. Whole exome was sequenced using, for the most part, Illumina TruSeq chemistry and Illumina HiSeq 2000 instrument, using 100 bp paired-end reads, according to the manufacturer's protocols. A mean of 75% of reads had coverage of at least 30-fold in both patients with PD and controls.

The human reference genome UCSC hg19 was used for sequence alignment and variant calling with the Burrows-Wheeler Aligner (http://bio-bwa.sourceforge.net/) and the Genome Analysis Toolkit (https://www.broadinstitute.org/gatk/). PCR duplicates were removed prior to variant calling using Picard software (http://broadinstitute.github.io/picard/). Variants were annotated with ANNOVAR software (http://www.openbioinformatics.org/annovar/).

Variants of interest were then verified by bidirectional Sanger sequencing using an ABI 3730 automated sequencer (Applied Biosystems, Life Technologies, Carlsbad, CA) with SeqScape v2.6 software (Applied Biosystems). Additional screening of the 2 RAB39B exons by direct sequencing was performed in a cohort of 192 unrelated French men with early-onset (EO) parkinsonism (mean age at onset 34.5 ± 7.6 years) recruited through the French network for the study of Parkinson disease genetics and 392 unrelated UK PD cases (mean age at onset 49.8 ± 14.2 years), including 48% men (mean age at onset 49.1 ± 14.4 years).

Standard protocol approvals, registrations, and patient consents.

Informed consent was obtained from all participants and the genetic studies were approved by local ethics committees.

Results.

Among the 1,348 patients with PD, we identified a single man of French origin with parkinsonism who harbored a novel nonsense mutation (c.557G>A in exon 2 [p.Trp186stop] of RAB39B) that was not found in 530 unrelated control individuals of European origin, public databases (dbSNP137) (http://www.ncbi.nlm.nih.gov/SNP/), or in an additional cohort of 61,486 unrelated individuals from the publicly available Exome Aggregation Consortium (http://exac.broadinstitute.org). In addition, this patient was excluded for mutations in all other known PD genes in data from exome analyses. Subsequent screening of RAB39B in 380 additional men with EO parkinsonism failed to identify any additional variants, suggesting that RAB39B is a very rare cause of parkinsonism.

The patient with the RAB39B p.Trp186stop mutation had early disease onset (39 years) and typical parkinsonism with asymmetric rest tremor, an akineto-rigid syndrome, and a good response to levodopa. He had mild mental retardation, which required sheltered employment. No other clinical abnormalities, such as pyramidal, cerebellar, or ocular disorders, were detected. No family history of PD was reported. Brain MRI performed twice was normal.

Eight years after disease onset, the patient developed treatment-related complications, including motor fluctuations, dyskinesia, and limb dystonia, and was thoroughly evaluated in view of possible deep brain stimulation. A neuropsychological examination showed good global cognitive performance (Mattis 138/144) but difficulty concentrating and subcortico-frontal signs. A psychiatric interview revealed dysthymic disorder with impulsiveness, explaining why surgery was ultimately not performed. Apomorphine treatment was initiated at age 55. The patient died the same year.

Discussion.

Previous studies showed RAB39B to be a rare cause of X-linked ID,3,–,6 which may be associated with autism spectrum disorder, epileptic seizures, and macrocephaly, but not parkinsonian signs. A recent study reported 2 families with loss-of-function mutations in RAB39B.2 All affected men from the 2 kindreds presented similar clinical phenotypes with variable degrees of ID in their childhood, including developmental delay, cognitive impairment, macroencephaly, and, in some, seizures; EO parkinsonism with tremor appeared subsequently as the presenting symptom. Neuropathologic examination was consistent with α-synuclein pathology. Although we could not exclude the presence of large and complex rearrangements undetectable by the exome sequencing method, we identified an RAB39B p.Trp186stop mutation carried by a 39-year-old man with parkinsonism. The case presented here extends the phenotype caused by loss-of-function RAB39B mutations to include X-linked typical EO parkinsonism with mental retardation that is mild enough to allow autonomous living. RAB39B plays a role in vesicular trafficking pathway, possibly affecting α-synuclein pathology, as recently reported for another PD-associated gene, VPS35.7

Acknowledgments

Acknowledgment: The authors are grateful to the patients and their families. They thank Merle Ruberg for critical reading of the manuscript and the DNA and Cell Bank of ICM for sample preparation.

Footnotes

  • The French Parkinson's Disease Genetics Study Group (PDG) and the International Parkinson's Disease Genomics Consortium (IPDGC) coinvestigators are listed at Neurology.org/ng.

  • Supplemental data at Neurology.org/ng

  • Author contributions: Dr. Lesage: drafting the manuscript, analysis and interpretation of data, and statistical analysis. Dr. Bras: acquisition, analysis, and interpretation of data. Dr. Cormier-Dequaire: acquisition of clinical data. Mrs. Condroyer: acquisition of genetic data. Dr. Nicolas: bioinformatics analyses. Mrs. Darwent, Dr. Guerreiro, Dr. Majounie, and Mrs. Federoff: exome data acquisition and analysis. Dr. Heutink, Dr. Wood, Dr. Gasser, and Dr. Hardy: acquisition and interpretation of data. Dr. Tison: acquisition of clinical data. Dr. Singleton: supervising the exome data acquisition, analyses and interpretation, and obtaining funding. Dr. Brice: drafting/revising the manuscript, study concept or design, study supervision, and obtaining funding. All authors critically reviewed and approved the final manuscript.

  • Study funding: Supported by the France-Parkinson Association, Roger de Spoelberch Foundation, and the French program “Investissements d'avenir” (ANR-10-IAIHU-06). This work was also supported in part by the Intramural Research Program of the National Institute on Aging, NIH, Department of Health and Human Services; project Z01 AG000958 and by MRC Grant G1100643/1.

  • Disclosure: Dr. Lesage, Dr. Bras, Dr. Cormier-Dequaire, Mrs. Condroyer, Dr. Nicolas, Mrs. Darwent, Dr. Guerreiro, Dr. Majounie, and Mrs. Federoff report no disclosures. Dr. Heutink has served on scientific advisory boards for Fondation Alzheimer France and Prices Beatrix Fonds; and holds patents for Pathogenic tau mutations, Diagnostics and therapeutics for autosomal dominant hemochromatosis, and a method for diagnosing a neurodegenerative disease. Dr. Wood reports no disclosures. Dr. Gasser has served on scientific advisory boards for joint programming in neurodegenerative disease; has received funding for travel and/or speaker honoraria from MedUpdate, Movement Disorders Society, and the Michael J. Fox Foundation; has served on the editorial boards of Parkinsonism and Related Disorders, Movement Disorders, and Journal of Neurology; holds patents for KASPP (LRRK2) Gene, its Production, and Use for the Detection and Treatment of Neurodegenerative Diseases; has served on speakers' bureaus for Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim, and Valeant Pharma; and has received research support from Novartis, MeFoPa, ERA-Net Neuron, MultiSyn, Courage-PD, Hemholz Association, and the Michael J. Fox Foundation. Dr. Hardy reports no disclosures. Dr. Tison has served on scientific advisory boards for Novartis, Boehringer-Ingelheim, GlaxoSmithKline, ABBOTT, and UCB; has received funding for travel and/or speaker honoraria from Lundbeck, Novartis, UCB, and TEVA; has consulted for Addex Pharma; and has received research support from Novartis, French Ministry of Health, University Hospital Bordeaux, and the Michael J. Fox Foundation. Dr. Singleton has received funding for travel and/or speaker honoraria from 23andMe; has served on the editorial boards of Annals of Neurology, Lancet Neurology, Neurogenetics, Neurodegenerative Diseases, Brain, and Journal of Parkinson's Disease; has a patent pending for panel of markers to diagnose stroke; and has received research support from NIH. Dr. Brice has received funding for travel and/or speaker honoraria from Lundbeck; and has received research support from Investissements d'avenir, Roger de Spoelberch Foundation, and France Parkinson Association. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the Inserm DR Paris 6.

  • Received April 12, 2015.
  • Accepted in final form May 19, 2015.
  • © 2015 American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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