Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.

Gaia Novarino ^# ¹, Ali G Fenstermaker ^# ¹, Maha S Zaki ^# ², Matan Hofree ³, Jennifer L Silhavy ¹, Andrew D Heiberg ¹, Mostafa Abdellateef ¹, Basak Rosti ¹, Eric Scott ¹, Lobna Mansour ⁴, Amira Masri ⁵, Hulya Kayserili ⁶, Jumana Y Al-Aama ⁷, Ghada M H Abdel-Salam ², Ariana Karminejad ⁸, Majdi Kara ⁹, Bulent Kara ¹⁰, Bita Bozorgmehri ⁸, Tawfeg Ben-Omran ¹¹, Faezeh Mojahedi ¹², Iman Gamal El Din Mahmoud ⁴, Naima Bouslam ¹³, Ahmed Bouhouche ¹³, Ali Benomar ¹³, Sylvain Hanein ¹⁴, Laure Raymond ¹⁴, Sylvie Forlani ¹⁴, Massimo Mascaro ¹, Laila Selim ⁴, Nabil Shehata ¹⁵, Nasir Al-Allawi ¹⁶, P S Bindu ¹⁷, Matloob Azam ¹⁸, Murat Gunel ¹⁹, Ahmet Caglayan ¹⁹, Kaya Bilguvar ¹⁹, Aslihan Tolun ²⁰, Mahmoud Y Issa ², Jana Schroth ¹, Emily G Spencer ¹, Rasim O Rosti ¹, Naiara Akizu ¹, Keith K Vaux ¹, Anide Johansen ¹, Alice A Koh ¹, Hisham Megahed ², Alexandra Durr ¹⁴ ²¹, Alexis Brice ¹⁴ ²¹ ²², Giovanni Stevanin ¹⁴ ²¹ ²² ²³, Stacy B Gabriel ²⁴, Trey Ideker ³, Joseph G Gleeson ¹

Affiliations

1 Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
2 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.
3 Department of Computer Science and Engineering and Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
4 Department of Pediatric Neurology, Neurometabolic Unit, Cairo University Children's Hospital, Cairo 406, Egypt.
5 Division of Child Neurology, Department of Pediatrics, University of Jordan, Amman 11942, Jordan.
6 Istanbul University, Istanbul Medical Faculty, Medical Genetics Department, 34093 Istanbul, Turkey.
7 Department of Genetic Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
8 Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
9 Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
10 Kocaeli University, Medical Faculty, Department of Pediatric Neurology, 41380 Umuttepe, Kocaeli, Turkey.
11 Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha 3050, Qatar.
12 Mashhad Medical Genetic Counseling Center, 91767 Mashhad, Iran.
13 Université Mohammed V Souissi, Equipe de Recherchéde Maladies Neurodégéneratives (ERMN) and Centre de Recherche en Épidémiologie Clinique et Essais Thérapeutiques (CRECET), 6402 Rabat, Morocco.
14 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.
15 Department of Pediatrics and Neonatology, Saudi German Hospital, Post Office Box 84348, Riyadh, Kingdom of Saudi Arabia.
16 Department of Pathology, School of Medicine, University of Dohuk, Dohuk, Iraq.
17 Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.
18 Department of Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan.
19 Department of Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
20 Department of Molecular Biology and Genetics, Bogazici University, 34342 Istanbul, Turkey.
21 Assistance Publique-Hôpitaux de Paris, Fédération de Génétique, Pitié-Salpêtrière Hospital, 75013 Paris, France.
22 Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France.
23 Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France.
24 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
# Contributed equally.

PMID: 24482476 DOI: 10.1126/science.1247363

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.

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