Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.
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.
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Gaia
G
Novarino
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Ali G
AG
Fenstermaker
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
Maha S
MS
Zaki
Department of Computer Science and Engineering and Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Matan
M
Hofree
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Jennifer L
JL
Silhavy
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Andrew D
AD
Heiberg
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Mostafa
M
Abdellateef
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Basak
B
Rosti
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Eric
E
Scott
Department of Pediatric Neurology, Neurometabolic Unit, Cairo University Children's Hospital, Cairo 406, Egypt.
Lobna
L
Mansour
Division of Child Neurology, Department of Pediatrics, University of Jordan, Amman 11942, Jordan.
Amira
A
Masri
Istanbul University, Istanbul Medical Faculty, Medical Genetics Department, 34093 Istanbul, Turkey.
Hulya
H
Kayserili
Department of Genetic Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Jumana Y
JY
Al-Aama
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
Ghada M H
GMH
Abdel-Salam
Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
Ariana
A
Karminejad
Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
Majdi
M
Kara
Kocaeli University, Medical Faculty, Department of Pediatric Neurology, 41380 Umuttepe, Kocaeli, Turkey.
Bulent
B
Kara
Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
Bita
B
Bozorgmehri
Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha 3050, Qatar.
Tawfeg
T
Ben-Omran
Mashhad Medical Genetic Counseling Center, 91767 Mashhad, Iran.
Faezeh
F
Mojahedi
Department of Pediatric Neurology, Neurometabolic Unit, Cairo University Children's Hospital, Cairo 406, Egypt.
Iman Gamal
IG
El Din Mahmoud
Université Mohammed V Souissi, Equipe de Recherchéde Maladies Neurodégéneratives (ERMN) and Centre de Recherche en Épidémiologie Clinique et Essais Thérapeutiques (CRECET), 6402 Rabat, Morocco.
Naima
N
Bouslam
Université Mohammed V Souissi, Equipe de Recherchéde Maladies Neurodégéneratives (ERMN) and Centre de Recherche en Épidémiologie Clinique et Essais Thérapeutiques (CRECET), 6402 Rabat, Morocco.
Ahmed
A
Bouhouche
Université Mohammed V Souissi, Equipe de Recherchéde Maladies Neurodégéneratives (ERMN) and Centre de Recherche en Épidémiologie Clinique et Essais Thérapeutiques (CRECET), 6402 Rabat, Morocco.
Ali
A
Benomar
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.
Sylvain
S
Hanein
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.
Laure
L
Raymond
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.
Sylvie
S
Forlani
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Massimo
M
Mascaro
Department of Pediatric Neurology, Neurometabolic Unit, Cairo University Children's Hospital, Cairo 406, Egypt.
Laila
L
Selim
Department of Pediatrics and Neonatology, Saudi German Hospital, Post Office Box 84348, Riyadh, Kingdom of Saudi Arabia.
Nabil
N
Shehata
Department of Pathology, School of Medicine, University of Dohuk, Dohuk, Iraq.
Nasir
N
Al-Allawi
Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.
P S
PS
Bindu
Department of Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan.
Matloob
M
Azam
Department of Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
Murat
M
Gunel
Department of Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
Ahmet
A
Caglayan
Department of Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
Kaya
K
Bilguvar
Department of Molecular Biology and Genetics, Bogazici University, 34342 Istanbul, Turkey.
Aslihan
A
Tolun
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
Mahmoud Y
MY
Issa
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Jana
J
Schroth
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Emily G
EG
Spencer
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Rasim O
RO
Rosti
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Naiara
N
Akizu
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Keith K
KK
Vaux
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Anide
A
Johansen
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Alice A
AA
Koh
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
Hisham
H
Megahed
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.
Alexandra
A
Durr
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.
Alexis
A
Brice
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.
Giovanni
G
Stevanin
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Stacy B
SB
Gabriel
Department of Computer Science and Engineering and Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Trey
T
Ideker
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Joseph G
JG
Gleeson
D000818:Animals; D001369:Axons / Q000502:physiology; D001692:Biological Transport / Q000235:genetics; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D006801:Humans; D016472:Motor Neuron Disease / Q000235:genetics*; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D009711:Nucleotides / Q000235:genetics / Q000378:metabolism; D011712:Pyramidal Tracts / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D013569:Synapses / Q000502:physiology; D059467:Transcriptome; D015027:Zebrafish
D009711:Nucleotides