Publications by authors named "Janel O Johnson"

28 Publications

  • Page 1 of 1

Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy.

J Clin Invest 2020 03;130(3):1506-1512

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target toxicities. Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2). Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Together, our findings highlight a critical role for JAG1 in maintaining peripheral nerve integrity, particularly in the recurrent laryngeal nerve, and provide a basis for the evaluation of peripheral neuropathy as part of the clinical development of Notch pathway-modulating therapeutics.
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http://dx.doi.org/10.1172/JCI128152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269582PMC
March 2020

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Authors:
Aude Nicolas Kevin P Kenna Alan E Renton Nicola Ticozzi Faraz Faghri Ruth Chia Janice A Dominov Brendan J Kenna Mike A Nalls Pamela Keagle Alberto M Rivera Wouter van Rheenen Natalie A Murphy Joke J F A van Vugt Joshua T Geiger Rick A Van der Spek Hannah A Pliner Shankaracharya Bradley N Smith Giuseppe Marangi Simon D Topp Yevgeniya Abramzon Athina Soragia Gkazi John D Eicher Aoife Kenna Gabriele Mora Andrea Calvo Letizia Mazzini Nilo Riva Jessica Mandrioli Claudia Caponnetto Stefania Battistini Paolo Volanti Vincenzo La Bella Francesca L Conforti Giuseppe Borghero Sonia Messina Isabella L Simone Francesca Trojsi Fabrizio Salvi Francesco O Logullo Sandra D'Alfonso Lucia Corrado Margherita Capasso Luigi Ferrucci Cristiane de Araujo Martins Moreno Sitharthan Kamalakaran David B Goldstein Aaron D Gitler Tim Harris Richard M Myers Hemali Phatnani Rajeeva Lochan Musunuri Uday Shankar Evani Avinash Abhyankar Michael C Zody Julia Kaye Steven Finkbeiner Stacia K Wyman Alex LeNail Leandro Lima Ernest Fraenkel Clive N Svendsen Leslie M Thompson Jennifer E Van Eyk James D Berry Timothy M Miller Stephen J Kolb Merit Cudkowicz Emily Baxi Michael Benatar J Paul Taylor Evadnie Rampersaud Gang Wu Joanne Wuu Giuseppe Lauria Federico Verde Isabella Fogh Cinzia Tiloca Giacomo P Comi Gianni Sorarù Cristina Cereda Philippe Corcia Hannu Laaksovirta Liisa Myllykangas Lilja Jansson Miko Valori John Ealing Hisham Hamdalla Sara Rollinson Stuart Pickering-Brown Richard W Orrell Katie C Sidle Andrea Malaspina John Hardy Andrew B Singleton Janel O Johnson Sampath Arepalli Peter C Sapp Diane McKenna-Yasek Meraida Polak Seneshaw Asress Safa Al-Sarraj Andrew King Claire Troakes Caroline Vance Jacqueline de Belleroche Frank Baas Anneloor L M A Ten Asbroek José Luis Muñoz-Blanco Dena G Hernandez Jinhui Ding J Raphael Gibbs Sonja W Scholz Mary Kay Floeter Roy H Campbell Francesco Landi Robert Bowser Stefan M Pulst John M Ravits Daniel J L MacGowan Janine Kirby Erik P Pioro Roger Pamphlett James Broach Glenn Gerhard Travis L Dunckley Christopher B Brady Neil W Kowall Juan C Troncoso Isabelle Le Ber Kevin Mouzat Serge Lumbroso Terry D Heiman-Patterson Freya Kamel Ludo Van Den Bosch Robert H Baloh Tim M Strom Thomas Meitinger Aleksey Shatunov Kristel R Van Eijk Mamede de Carvalho Maarten Kooyman Bas Middelkoop Matthieu Moisse Russell L McLaughlin Michael A Van Es Markus Weber Kevin B Boylan Marka Van Blitterswijk Rosa Rademakers Karen E Morrison A Nazli Basak Jesús S Mora Vivian E Drory Pamela J Shaw Martin R Turner Kevin Talbot Orla Hardiman Kelly L Williams Jennifer A Fifita Garth A Nicholson Ian P Blair Guy A Rouleau Jesús Esteban-Pérez Alberto García-Redondo Ammar Al-Chalabi Ekaterina Rogaeva Lorne Zinman Lyle W Ostrow Nicholas J Maragakis Jeffrey D Rothstein Zachary Simmons Johnathan Cooper-Knock Alexis Brice Stephen A Goutman Eva L Feldman Summer B Gibson Franco Taroni Antonia Ratti Cinzia Gellera Philip Van Damme Wim Robberecht Pietro Fratta Mario Sabatelli Christian Lunetta Albert C Ludolph Peter M Andersen Jochen H Weishaupt William Camu John Q Trojanowski Vivianna M Van Deerlin Robert H Brown Leonard H van den Berg Jan H Veldink Matthew B Harms Jonathan D Glass David J Stone Pentti Tienari Vincenzo Silani Adriano Chiò Christopher E Shaw Bryan J Traynor John E Landers

Neuron 2018 03;97(6):1268-1283.e6

Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address:

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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http://dx.doi.org/10.1016/j.neuron.2018.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867896PMC
March 2018

Exome sequencing establishes a gelsolin mutation as the cause of inherited bulbar-onset neuropathy.

Muscle Nerve 2017 Nov 23;56(5):1001-1005. Epub 2017 Mar 23.

Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Introduction: Progressive bulbar motor neuropathy is primarily caused by bulbar-onset ALS. Hereditary amyloidosis type IV also presents with a bulbar neuropathy that mimics motor neuron disease. The disease is prevalent in Finland only and is not commonly included in the differential diagnosis of ALS.

Methods: We studied 18 members of a family in which some had bulbar motor neuropathy, and we performed exome sequencing.

Results: Five affected family members were found to have a D187Y substitution in the GSN gene known to cause hereditary amyloidosis type IV.

Conclusions: This American family presented with progressive bulbar neuropathy due to a gelsolin mutation not found in Finland. Hereditary amyloidosis type IV presents with bulbar motor neuropathy and not with peripheral neuropathy as occurs with common forms of amyloidosis. This report demonstrates the power of exome sequencing to determine the cause of rare hereditary diseases with incomplete or atypical phenotypes. Muscle Nerve 56: 1001-1005, 2017.
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http://dx.doi.org/10.1002/mus.25550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494018PMC
November 2017

ATNX2 is not a regulatory gene in Italian amyotrophic lateral sclerosis patients with C9ORF72 GGGGCC expansion.

Neurobiol Aging 2016 Mar 8;39:218.e5-8. Epub 2015 Dec 8.

Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, Italy.

There are indications that both familial amyotrophic lateral sclerosis (ALS) and sporadic ALS phenotype and prognosis are partly regulated by genetic and environmental factors, supporting the theory that ALS is a multifactorial disease. The aim of this article was to assess the role of ATXN2 intermediate length repeats in a large series of Italian and Sardinian ALS patients and controls carrying a pathogenetic C9ORF72 GGGGCC hexanucleotide repeat. A total of 1972 ALS cases were identified through the database of the Italian ALS Genetic consortium, a collaborative effort including 18 ALS centers throughout Italy. The study population included: (1) 276 Italian and 57 Sardinian ALS cases who carried the C9ORF72 expansion; (2) 1340 Italian and 299 Sardinian ALS cases not carrying the C9ORF72 expansion. A total of healthy 1043 controls were also assessed. Most Italian and Sardinian cases and controls were homozygous for 22/22 or 23/23 repeats or heterozygous for 22/23 repeats of the ATXN2 gene. ATXN2 intermediate length repeats alleles (≥28) were detected in 3 (0.6%) Italian ALS cases carrying the C9ORF72 expansion, in none of the Sardinian ALS cases carrying the expansion, in 60 (4.3%) Italian cases not carrying the expansion, and in 6 (2.0%) Sardinian ALS cases without C9ORF72 expansion. Intermediate length repeat alleles were found in 12 (1.5%) Italian controls and 1 (0.84%) Sardinian controls. Therefore, ALS patients with C9ORF72 expansion showed a lower frequency of ATXN2 polyQ intermediate length repeats than both controls (Italian cases, p = 0.137; Sardinian cases, p = 0.0001) and ALS patients without C9ORF72 expansion (Italian cases, p = 0.005; Sardinian cases, p = 0.178). In our large study on Italian and Sardinian ALS patients with C9ORF72 GGGGCC hexanucleotide repeat expansion, compared to age-, gender- and ethnic-matched controls, ATXN2 polyQ intermediate length does not represent a modifier of ALS risk, differently from non-C9ORF72 mutated patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775342PMC
March 2016

HFE p.H63D polymorphism does not influence ALS phenotype and survival.

Neurobiol Aging 2015 Oct 18;36(10):2906.e7-11. Epub 2015 Jun 18.

Laboratory of Molecular Genetics, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy.

It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5183653PMC
October 2015

Association of a Novel ACTA1 Mutation With a Dominant Progressive Scapuloperoneal Myopathy in an Extended Family.

JAMA Neurol 2015 Jun;72(6):689-98

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

Importance: New genomic strategies can now be applied to identify a diagnosis in patients and families with previously undiagnosed rare genetic conditions. The large family evaluated in the present study was described in 1966 and now expands the phenotype of a known neuromuscular gene.

Objective: To determine the genetic cause of a slowly progressive, autosomal dominant, scapuloperoneal neuromuscular disorder by using linkage and exome sequencing.

Design, Setting, And Participants: Fourteen affected individuals in a 6-generation family with a progressive scapuloperoneal disorder were evaluated. Participants were examined at pediatric, neuromuscular, and research clinics from March 1, 2005, to May 31, 2014. Exome and linkage were performed in genetics laboratories of research institutions.

Main Outcomes And Measures: Examination and evaluation by magnetic resonance imaging, ultrasonography, electrodiagnostic studies, and muscle biopsies (n = 3). Genetic analysis included linkage analysis (n = 17) with exome sequencing (n = 7).

Results: Clinical findings included progressive muscle weakness in an initially scapuloperoneal and distal distribution, including wrist extensor weakness, finger and foot drop, scapular winging, mild facial weakness, Achilles tendon contractures, and diminished or absent deep tendon reflexes. Both age at onset and progression of the disease showed clinical variability within the family. Muscle biopsy specimens demonstrated type I fiber atrophy and trabeculated fibers without nemaline rods. Analysis of exome sequences within the linkage region (4.8 megabases) revealed missense mutation c.591C>A p.Glu197Asp in a highly conserved residue in exon 4 of ACTA1. The mutation cosegregated with disease in all tested individuals and was not present in unaffected individuals.

Conclusions And Relevance: This family defines a new scapuloperoneal phenotype associated with an ACTA1 mutation. A highly conserved protein, ACTA1 is implicated in multiple muscle diseases, including nemaline myopathy, actin aggregate myopathy, fiber-type disproportion, and rod-core myopathy. To our knowledge, mutations in Glu197 have not been reported previously. This residue is highly conserved and located in an exposed position in the protein; the mutation affects the intermolecular and intramolecular electrostatic interactions as shown by structural modeling. The mutation in this residue does not appear to lead to rod formation or actin accumulation in vitro or in vivo, suggesting a different molecular mechanism from that of other ACTA1 diseases.
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http://dx.doi.org/10.1001/jamaneurol.2015.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461456PMC
June 2015

Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.

JAMA Neurol 2015 May;72(5):561-70

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

Importance: The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients.

Objective: To identify the genetic cause for a novel form of pure autosomal dominant HSP.

Design, Setting, And Participants: We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened.

Main Outcome And Measure: Mutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene.

Results: We identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P < .01) and size (0.29 [0.01] vs 0.26 [0.01]; P < .05) of lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c-/- mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P < .001), suggesting a dominant negative mechanism for the mutation.

Conclusions And Relevance: This study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.
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http://dx.doi.org/10.1001/jamaneurol.2014.4769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612424PMC
May 2015

CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients.

Neurobiol Aging 2015 Apr 28;36(4):1767.e3-1767.e6. Epub 2015 Jan 28.

NEuroMuscular Omnicenter, Serena Onlus Foundation, Milan, Italy.

Mutations in CHCHD10 have recently been described as a cause of frontotemporal dementia (FTD) comorbid with amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the frequency and clinical characteristics of CHCHD10 mutations in Italian patients diagnosed with familial (n = 64) and apparently sporadic ALS (n = 224). Three apparently sporadic patients were found to carry c.100C>T (p.Pro34Ser) heterozygous variant in the exon 2 of CHCHD10. This mutation had been previously described in 2 unrelated French patients with FTD-ALS. However, our patients had a typical ALS, without evidence of FTD, cerebellar or extrapyramidal signs, or sensorineural deficits. We confirm that CHCHD10 mutations account for ∼ 1% of Italian ALS patients and are a cause of disease in subjects without dementia or other atypical clinical signs.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380794PMC
April 2015

A genome-wide association study of myasthenia gravis.

JAMA Neurol 2015 Apr;72(4):396-404

Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland11Department of Neurology, Johns Hopkins School of Medicine, Baltimore, M.

Importance: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood.

Objective: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study.

Design, Setting, And Participants: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication.

Main Outcomes And Measures: We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing.

Results: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases.

Conclusions And Relevance: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.
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http://dx.doi.org/10.1001/jamaneurol.2014.4103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856525PMC
April 2015

Small deletion in C9orf72 hides a proportion of expansion carriers in FTLD.

Neurobiol Aging 2015 Mar 12;36(3):1601.e1-5. Epub 2014 Dec 12.

Faculty of Human and Medical Sciences, Institute of Brain Behaviour and Mental Health, University of Manchester, Manchester, UK. Electronic address:

Frontotemporal lobar degeneration is a highly familial disease and the most common known genetic cause is the repeat expansion mutation in the gene C9orf72. We have identified 2 brothers with an expansion mutation in C9orf72 using Southern blotting that is undetectable using repeat-primed polymerase chain reaction. Sequencing using high concentrations of DNA denaturants of a bacterial artificial chromosome clone obtained from one of the brothers identified a 10-base pair deletion adjacent to the expansion that presumably confers strong secondary structure that interferes with the genotyping. Using an alternative method, we have identified missed expansion carriers in our cohort, and this number has increased by approximately 25%. This observation has important implications for patients undergoing genetic testing for C9orf72.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353501PMC
March 2015

A 7.5-Mb duplication at chromosome 11q21-11q22.3 is associated with a novel spastic ataxia syndrome.

Mov Disord 2015 Feb 27;30(2):262-6. Epub 2014 Dec 27.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Molecular Neuroscience and Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, Queen Square, London, UK.

Background: The autosomal dominant spinocerebellar ataxias are most commonly caused by nucleotide repeat expansions followed by base-pair changes in functionally important genes. Structural variation has recently been shown to underlie spinocerebellar ataxia types 15 and 20.

Methods: We applied single-nucleotide polymorphism (SNP) genotyping to determine whether structural variation causes spinocerebellar ataxia in a family from France.

Results: We identified an approximately 7.5-megabasepair duplication on chromosome 11q21-11q22.3 that segregates with disease. This duplication contains an estimated 44 genes. Duplications at this locus were not found in control individuals.

Conclusions: We have identified a new spastic ataxia syndrome caused by a genomic duplication, which we have denoted as spinocerebellar ataxia type 39. Finding additional families with this phenotype will be important to identify the genetic lesion underlying disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318767PMC
http://dx.doi.org/10.1002/mds.26059DOI Listing
February 2015

Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis.

Brain 2014 Dec 26;137(Pt 12):e311. Epub 2014 Sep 26.

1 Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA

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http://dx.doi.org/10.1093/brain/awu265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240285PMC
December 2014

Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis.

Nat Neurosci 2014 May 30;17(5):664-666. Epub 2014 Mar 30.

Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA.

MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.
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http://dx.doi.org/10.1038/nn.3688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000579PMC
May 2014

Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.

Hum Mutat 2013 Oct 12;34(10):1357-60. Epub 2013 Aug 12.

Service de Neurologie, Centre Hospitalier Universitaire du Point "G", Bamako, Mali; Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.
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http://dx.doi.org/10.1002/humu.22378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819934PMC
October 2013

A candidate gene for autoimmune myasthenia gravis.

Neurology 2012 Jul 27;79(4):342-7. Epub 2012 Jun 27.

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Objective: We sought to identify a causative mutation in a previously reported kindred with parental consanguinity and 5 of 10 siblings with adult-onset autoimmune myasthenia gravis.

Methods: We performed genome-wide homozygosity mapping, and sequenced all known genes in the one region of extended homozygosity. Quantitative and allele-specific reverse transcriptase PCR (RT-PCR) were performed on a candidate gene to determine the RNA expression level in affected siblings and controls and the relative abundance of the wild-type and mutant alleles in a heterozygote.

Results: A region of shared homozygosity at chromosome 13q13.3-13q14.11 was found in 4 affected siblings and 1 unaffected sibling. A homozygous single nucleotide variant was found in the 3'-untranslated region of the ecto-NADH oxidase 1 gene (ENOX1). No other variants likely to be pathogenic were found in genes in this region or elsewhere. The ENOX1 sequence variant was not found in 764 controls. Quantitative RT-PCR showed that expression of ENOX1 decreased to about 20% of normal levels in lymphoblastoid cells from individuals homozygous for the variant and to about 50% in 2 unaffected heterozygotes. Allele-specific RT-PCR showed a 55%-60% reduction in the level of the variant transcript in heterozygous cells due to reduced mRNA stability.

Conclusion: These results indicate that this sequence variant in ENOX1 may contribute to the familial autoimmune myasthenia in these patients.
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http://dx.doi.org/10.1212/WNL.0b013e318260cbd0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400092PMC
July 2012

Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.

Brain 2012 Sep 26;135(Pt 9):2875-82. Epub 2012 Jun 26.

Laboratory of Neurogenetics, National Institute on Ageing, National Institutes of Health, Bethesda, MD 20892, USA.

Brown-Vialetto-Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown-Vialetto-Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown-Vialetto-Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown-Vialetto-Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results.
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http://dx.doi.org/10.1093/brain/aws161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437022PMC
September 2012

Exome sequencing in an SCA14 family demonstrates its utility in diagnosing heterogeneous diseases.

Neurology 2012 Jul 6;79(2):127-31. Epub 2012 Jun 6.

Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, UK.

Objective: Genetic heterogeneity is common in many neurologic disorders. This is particularly true for the hereditary ataxias where at least 36 disease genes or loci have been described for spinocerebellar ataxia and over 100 genes for neurologic disorders that present primarily with ataxia. Traditional genetic testing of a large number of candidate genes delays diagnosis and is expensive. In contrast, recently developed genomic techniques, such as exome sequencing that targets only the coding portion of the genome, offer an alternative strategy to rapidly sequence all genes in a comprehensive manner. Here we describe the use of exome sequencing to investigate a large, 5-generational British kindred with an autosomal dominant, progressive cerebellar ataxia in which conventional genetic testing had not revealed a causal etiology.

Methods: Twenty family members were seen and examined; 2 affected individuals were clinically investigated in detail without a genetic or acquired cause being identified. Exome sequencing was performed in one patient where coverage was comprehensive across the known ataxia genes, excluding the known repeat loci which should be examined using conventional analysis.

Results: A novel p.Arg26Gly change in the PRKCG gene, mutated in SCA14, was identified. This variant was confirmed using Sanger sequencing and showed segregation with disease in the entire family.

Conclusions: This work demonstrates the utility of exome sequencing to rapidly screen heterogeneous genetic disorders such as the ataxias. Exome sequencing is more comprehensive, faster, and significantly cheaper than conventional Sanger sequencing, and thus represents a superior diagnostic screening tool in clinical practice.
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http://dx.doi.org/10.1212/WNL.0b013e31825f048eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390538PMC
July 2012

Valosin-containing protein (VCP) mutations in sporadic amyotrophic lateral sclerosis.

Neurobiol Aging 2012 Sep 8;33(9):2231.e1-2231.e6. Epub 2012 May 8.

Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.

We recently reported that mutations in the valosin-containing protein (VCP) gene are a cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three U.S. cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS but account for <1% of this form of disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2012.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391327PMC
September 2012

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

Lancet Neurol 2012 Apr 9;11(4):323-30. Epub 2012 Mar 9.

Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

Background: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Methods: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion.

Findings: In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years.

Interpretation: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.

Funding: Full funding sources listed at end of paper (see Acknowledgments).
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http://dx.doi.org/10.1016/S1474-4422(12)70043-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322422PMC
April 2012

A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.

Neuron 2011 Oct 21;72(2):257-68. Epub 2011 Sep 21.

Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
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http://dx.doi.org/10.1016/j.neuron.2011.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200438PMC
October 2011

SCA15 due to large ITPR1 deletions in a cohort of 333 white families with dominant ataxia.

Arch Neurol 2011 May;68(5):637-43

INSERM U975, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, Groupe Hospitalier Pitié Salpêtrière, 47 Boulevard de l'Hôpital, Paris Cedex 13, France.

Background: Deletions in ITPR1, coding for the inositol-triphosphate receptor type 1, have been recently identified in spinocerebellar ataxia type 15 (SCA15).

Objective: To determine the frequency and the phenotypical spectrum of SCA15.

Design: Taqman polymerase chain reaction (258 index cases) or single-nucleotide polymorphism genome-wide genotyping (75 index cases).

Setting: A collaboration between the Centre de Recherche de l'Institut de Cerveau et de la Moelle Epinière of the Salpêtrière Hospital (Paris, France) and the Molecular Genetics Unit of the National Institute of Aging (Bethesda, Maryland). Patients  Index cases of 333 families with autosomal dominant cerebellar ataxia negative for CAG repeat expansions in coding exons.

Main Outcome Measures: Detection of ITPR1 copy number alterations.

Results: A deletion of ITPR1 was found in 6 of 333 families (1.8%), corresponding to 13 patients with SCA15. Age at onset ranged from 18 to 66 years (mean [SD] age, 35 [16] years). The symptom at onset was cerebellar gait ataxia, except in 1 patient with isolated upper limb tremor. Although families were tested irrespective of their phenotype, patients with SCA15 had a homogeneous phenotype and were characterized by a slowly progressive cerebellar ataxia. However, pyramidal signs (2 patients) and mild cognitive problems (2 patients) were occasionally present. Radiologic findings showed global or predominant vermian cerebellar atrophy in all patients.

Conclusions: In this series, ITPR1 deletions were rare and accounted for approximately 1% of all autosomal dominant cerebellar ataxias. The SCA15 phenotype mostly consists of a slowly progressive isolated cerebellar ataxia with variable age at onset; an additional pyramidal syndrome and problems in executive functions may be present.
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http://dx.doi.org/10.1001/archneurol.2011.81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3142680PMC
May 2011

Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene.

Arch Neurol 2011 May 10;68(5):594-8. Epub 2011 Jan 10.

Department of Neuroscience, University of Torino, Via Cherasco 15, Turin, Italy.

Objective: To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)-related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.

Design: Population-based, prospective cohort study.

Patients: A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.

Intervention: Patients underwent mutational analysis for SOD1, FUS, and TARDBP.

Results: Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144G>A (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94-single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness.

Conclusions: The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.
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http://dx.doi.org/10.1001/archneurol.2010.352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513278PMC
May 2011

Exome sequencing reveals VCP mutations as a cause of familial ALS.

Neuron 2010 Dec;68(5):857-64

Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, Porter Neuroscience Building, NIA, NIH, Bethesda, MD 20892, USA.

Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.
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http://dx.doi.org/10.1016/j.neuron.2010.11.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032425PMC
December 2010

Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients.

Proc Natl Acad Sci U S A 2010 Jul 21;107(27):12335-8. Epub 2010 Jun 21.

Molecular Genetics Section, and Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.

It was recently reported that rs1541160 on chromosome 1q24.2 has a marked effect on survival of amyotrophic lateral sclerosis (ALS) patients by influencing KIFAP3 expression. The cohorts used in that study were collected from ALS specialty clinics. We attempted to replicate these findings in a population-based cohort of 504 Italian ALS patients. None of 140 SNPs genotyped within the KIFAP3 locus (including rs1541160) had an effect on survival (log-rank P value for rs1541160 = 0.47) or on gene expression in that region. These data illustrate the complexities associated with analyzing ALS phenotypes for association.
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http://dx.doi.org/10.1073/pnas.0914079107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901467PMC
July 2010

Smoking-responsive juvenile-onset Parkinsonism.

Mov Disord 2007 Jan;22(1):115-9

Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

We describe a patient with juvenile levodopa-responsive Parkinsonism who reported a dramatic response to cigarette smoking with transient but marked improvement of motor symptoms associated with oculogyric crises and psychotic behavior. His beta-CIT single-photon emission computed tomography scan showed a complete absence of presynaptic dopaminergic nerve terminals.
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http://dx.doi.org/10.1002/mds.21177DOI Listing
January 2007

Parkin disease in a Brazilian kindred: Manifesting heterozygotes and clinical follow-up over 10 years.

Mov Disord 2005 Apr;20(4):479-84

Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, United Kingdom.

We report on a large Brazilian kindred with young-onset parkinsonism due to either a homozygous or heterozygous mutation in parkin. A total of 6 members were affected: 5 were homozygous and 1 heterozygous for a deletion in exon 4. Two other heterozygotes also had extrapyramidal signs. All affected subjects showed characteristic features of parkin disease with foot dystonia and an excellent response to levodopa complicated by motor fluctuations and dyskinesia within 3 years of therapy. Careful clinical follow-up over 10 years showed the phenotype was similar in all the homozygotes with asymmetrical limb bradykinesia and early walking difficulties. Some acceleration of disability was observed in some of the cases as they entered the third decade of illness, but dementia was absent.
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http://dx.doi.org/10.1002/mds.20335DOI Listing
April 2005