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PMID: 24482476 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.

Science (New York, N.Y.) ·Vol. 343 ·No. 6170 ·2014-01-31 ·Pages 506-511

Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GMH, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, El Din Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG

Abstract

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

MeSH Terms
Animals Axons/physiology Biological Transport/genetics Cohort Studies Exome/genetics Gene Regulatory Networks Genetic Association Studies Humans Motor Neuron Disease/genetics Mutation Neurons/metabolism Nucleotides/genetics,metabolism Pyramidal Tracts/metabolism Sequence Analysis, DNA Spastic Paraplegia, Hereditary/genetics Synapses/physiology Transcriptome Zebrafish
Chemicals
Nucleotides
Authors & Affiliations
52 authors, click to expand affiliations / ORCID
Novarino Gaia
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Fenstermaker Ali G
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Zaki Maha S
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
Hofree Matan
Department of Computer Science and Engineering and Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Silhavy Jennifer L
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Heiberg Andrew D
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Abdellateef Mostafa
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Rosti Basak
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Scott Eric
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Mansour Lobna
Department of Pediatric Neurology, Neurometabolic Unit, Cairo University Children's Hospital, Cairo 406, Egypt.
Masri Amira
Division of Child Neurology, Department of Pediatrics, University of Jordan, Amman 11942, Jordan.
Kayserili Hulya
Istanbul University, Istanbul Medical Faculty, Medical Genetics Department, 34093 Istanbul, Turkey.
Al-Aama Jumana Y
Department of Genetic Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Abdel-Salam Ghada M H
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
Karminejad Ariana
Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
Kara Majdi
Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
Kara Bulent
Kocaeli University, Medical Faculty, Department of Pediatric Neurology, 41380 Umuttepe, Kocaeli, Turkey.
Bozorgmehri Bita
Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
Ben-Omran Tawfeg
Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha 3050, Qatar.
Mojahedi Faezeh
Mashhad Medical Genetic Counseling Center, 91767 Mashhad, Iran.
El Din Mahmoud Iman Gamal
Department of Pediatric Neurology, Neurometabolic Unit, Cairo University Children's Hospital, Cairo 406, Egypt.
Bouslam Naima
Université Mohammed V Souissi, Equipe de Recherchéde Maladies Neurodégéneratives (ERMN) and Centre de Recherche en Épidémiologie Clinique et Essais Thérapeutiques (CRECET), 6402 Rabat, Morocco.
Bouhouche Ahmed
Université Mohammed V Souissi, Equipe de Recherchéde Maladies Neurodégéneratives (ERMN) and Centre de Recherche en Épidémiologie Clinique et Essais Thérapeutiques (CRECET), 6402 Rabat, Morocco.
Benomar Ali
Université Mohammed V Souissi, Equipe de Recherchéde Maladies Neurodégéneratives (ERMN) and Centre de Recherche en Épidémiologie Clinique et Essais Thérapeutiques (CRECET), 6402 Rabat, Morocco.
Hanein Sylvain
Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225; UPMC Univ Paris VI UMR_S975, 75013 Paris, France.
Raymond Laure
Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225; UPMC Univ Paris VI UMR_S975, 75013 Paris, France.
Forlani Sylvie
Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225; UPMC Univ Paris VI UMR_S975, 75013 Paris, France.
Mascaro Massimo
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Selim Laila
Department of Pediatric Neurology, Neurometabolic Unit, Cairo University Children's Hospital, Cairo 406, Egypt.
Shehata Nabil
Department of Pediatrics and Neonatology, Saudi German Hospital, Post Office Box 84348, Riyadh, Kingdom of Saudi Arabia.
Al-Allawi Nasir
Department of Pathology, School of Medicine, University of Dohuk, Dohuk, Iraq.
Bindu P S
Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.
Azam Matloob
Department of Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan.
Gunel Murat
Department of Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
Caglayan Ahmet
Department of Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
Bilguvar Kaya
Department of Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
Tolun Aslihan
Department of Molecular Biology and Genetics, Bogazici University, 34342 Istanbul, Turkey.
Issa Mahmoud Y
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
Schroth Jana
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Spencer Emily G
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Rosti Rasim O
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Akizu Naiara
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Vaux Keith K
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Johansen Anide
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Koh Alice A
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Megahed Hisham
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
Durr Alexandra
Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225; UPMC Univ Paris VI UMR_S975, 75013 Paris, France. | Assistance Publique-Hôpitaux de Paris, Fédération de Génétique, Pitié-Salpêtrière Hospital, 75013 Paris, France.
Brice Alexis
Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225; UPMC Univ Paris VI UMR_S975, 75013 Paris, France. | Assistance Publique-Hôpitaux de Paris, Fédération de Génétique, Pitié-Salpêtrière Hospital, 75013 Paris, France. | Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France.
Stevanin Giovanni
Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225; UPMC Univ Paris VI UMR_S975, 75013 Paris, France. | Assistance Publique-Hôpitaux de Paris, Fédération de Génétique, Pitié-Salpêtrière Hospital, 75013 Paris, France. | Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France. | Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France.
Gabriel Stacy B
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Ideker Trey
Department of Computer Science and Engineering and Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Gleeson Joseph G
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1247363
Published
2014-01-31
Pages
506-511
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC4157572
Subset
IM
Grants
NINDS NIH HHS · R01 NS048453 · United States
NICHD NIH HHS · P01HD070494 · United States
NCI NIH HHS · N01CO12400 · United States
NHGRI NIH HHS · U54 HG003067 · United States
NINDS NIH HHS · P30NS047101 · United States
NINDS NIH HHS · R01NS048453 · United States
NINDS NIH HHS · P30 NS047101 · United States
NIGMS NIH HHS · P41 GM103504 · United States
NHLBI NIH HHS · HHSN268201100011I · United States
Howard Hughes Medical Institute · United States
NHLBI NIH HHS · HHSN268201100011C · United States
NHGRI NIH HHS · U54HG003067 · United States
NINDS NIH HHS · R01 NS041537 · United States
NHGRI NIH HHS · U54HG006504 · United States
NHGRI NIH HHS · HHSN268200782096C · United States
NHGRI NIH HHS · U54 HG006504 · United States
NINDS NIH HHS · R01 NS052455 · United States
NICHD NIH HHS · P01 HD070494 · United States
NCI NIH HHS · N01-CO-12400 · United States
PHS HHS · HHSN268201100011 · United States
NINDS NIH HHS · R01NS041537 · United States
NINDS NIH HHS · R01NS052455 · United States
Databases
dbGaP
PHS000288
Corrections
CommentIn
PMID: 24482474
CommentIn
PMID: 24566998
CommentIn
PMID: 24797999
External Links
PubMed source DOI: 10.1126/science.1247363 PMC Full Text View journal details
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