Discovery doubles number of HSP causes

Genes never before linked with human disease found


Scientists discover new genetic forms of neurodegeneration


Joseph Gleeson
Joseph Gleeson

In a study published in the January 31, 2014 issue of Science, an international team led by scientists at the University of California, San Diego School of Medicine report doubling the number of known causes for the neurodegenerative disorder known as hereditary spastic paraplegia. HSP is characterized by progressive stiffness and contraction of the lower limbs and is associated with epilepsy, cognitive impairment, blindness and other neurological features.


Over several years, working with scientific colleagues in parts of the world with relatively high rates of consanguinity or common ancestry, UC San Diego researchers recruited a cohort of more than 50 families displaying autosomal recessive HSP – the largest such cohort assembled to date.

The scientists analyzed roughly 100 patients from this cohort using a technique called whole exome sequencing, which focuses on mapping key portions of the genome. They identified a genetic mutation in almost 75 percent of the cases, half of which were in genes never before linked with human disease.

“After uncovering so many novel genetic bases of HSP, we were in the unique position to investigate how these causes link together. We were able to generate an ‘HSP-ome,’ a map that included all of the new and previously described causes,” said senior author Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children’s Hospital-San Diego, a research affiliate of UC San Diego.

The HSP-ome helped researchers locate and validate even more genetic mutations in their patients, and indicated key biological pathways underlying HSP. The researchers were also interested in understanding how HSP relates to other groups of disorders. They found that the HSP-ome links HSP to other more common neurodegenerative disorders, such as Alzheimer’s disease and amyotrophic lateral sclerosis.

“Knowing the biological processes underlying neurodegenerative disorders is seminal to driving future scientific studies that aim to uncover the exact mechanisms implicated in common neurodegenerative diseases, and to indicate the path toward development of effective treatments,” said Gleeson.

“I believe this study is important for the neurodegenerative research community,” said co-lead author Gaia Novarino, PhD, a post-doctoral scholar in Gleeson’s lab. “But more broadly, it offers an illustrative example of how, by utilizing genomics in specific patient populations, and then building an ‘interactome,’ we greatly expand knowledge around unknown causes of disease.”

“This is very exciting since identifying the biological processes in neurological disorders is the first step toward the development of new treatments,” agreed co-lead author Ali G. Fenstermaker. “We identified several promising targets for development of new treatments.”

… from a press release of the University of California, San Diego, 30 Jan 2014



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.


SOURCE:  Science. 2014 Jan 31;343(6170):506-11. doi: 10.1126/science.1247363.  PMID: 24482476 [PubMed – in process]

Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders

Gaia Novarino1,*,, Ali G. Fenstermaker1,*, Maha S. Zaki3,*, Matan Hofree2, Jennifer L. Silhavy1, Andrew D. Heiberg1, Mostafa Abdellateef1, Basak Rosti1, Eric Scott1, Lobna Mansour4, Amira Masri5, Hulya Kayserili6, Jumana Y. Al-Aama7, Ghada M. H. Abdel-Salam3, Ariana Karminejad8, Majdi Kara9, Bulent Kara10, Bita Bozorgmehri8, Tawfeg Ben-Omran11, Faezeh Mojahedi12, Iman Gamal El Din Mahmoud4, Naima Bouslam13, Ahmed Bouhouche13, Ali Benomar13, Sylvain Hanein14, Laure Raymond14, Sylvie Forlani14, Massimo Mascaro1, Laila Selim4, Nabil Shehata15, Nasir Al-Allawi16, P.S. Bindu17, Matloob Azam18, Murat Gunel19, Ahmet Caglayan19, Kaya Bilguvar19, Aslihan Tolun20, Mahmoud Y. Issa3, Jana Schroth1, Emily G. Spencer1, Rasim O. Rosti1, Naiara Akizu1, Keith K. Vaux1, Anide Johansen1, Alice A. Koh1, Hisham Megahed3, Alexandra Durr14,21, Alexis Brice14,21,22, Giovanni Stevanin14,21,22,23, Stacy B. Gabriel24, Trey Ideker2, Joseph G. Gleeson1,

1Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA   92093, USA.

2Department of Computer Science and Engineering and Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

3Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo 12311, Egypt.

4Department of Pediatric Neurology, Neurometabolic Unit, Cairo University Children’s Hospital, Cairo 406, Egypt.

5Division of Child Neurology, Department of Pediatrics, University of Jordan, Amman 11942, Jordan.

6Istanbul University, Istanbul Medical Faculty, Medical Genetics Department, 34093 Istanbul, Turkey.

7Department of Genetic Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

8Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.

9Department of Pediatrics, Tripoli Children’s Hospital, Tripoli, Libya.

10Kocaeli University, Medical Faculty, Department of Pediatric Neurology, 41380 Umuttepe, Kocaeli, Turkey.

11Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha 3050, Qatar.

12Mashhad Medical Genetic Counseling Center, 91767 Mashhad, Iran.

13Université Mohammed V Souissi, Equipe de Recherché de Maladies Neurodégéneratives (ERMN) and Centre de Recherche en Épidémiologie Clinique et Essais Thérapeutiques (CRECET), 6402 Rabat, Morocco.

14Centre 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.

15Department of Pediatrics and Neonatology, Saudi German Hospital, Post Office Box 84348, Riyadh, Kingdom of Saudi Arabia.

16Department of Pathology, School of Medicine, University of Dohuk, Dohuk, Iraq.

17Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.

18Department of Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan.

19Department of Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.

20Department of Molecular Biology and Genetics, Bogazici University, 34342 Istanbul, Turkey.

21Assistance Publique–Hôpitaux de Paris, Fédération de Génétique, Pitié-Salpêtrière Hospital, 75013 Paris, France.

22Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France.

23Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France.

24Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

1 comment

  1. Yes I have this dreadful disease, I had it when I was 41 years of age and now I`m 53 years old. I have had afo`s for my feet, but they only masked the problem even more. It is in my lower limbs, I`m losing muscle mass in my legs, when I fall I pull myself up to stand again, my legs feel like they are 3,000 pounds trying to lift up. I walk with a cane, but I have a will to live and keep going. I played (ice) hockey my young life, and I still want to lace up my skates to play again. My feet drag all the time when I walk. My neurologists were giving my other brothers baclofen, muscle relaxer. One of my brothers took so much of that pill he couldn`t pee, so the doctors put a catheter in his penis, he was so weak, he didn`t want to exercise, end result he passed away last march. I will fight this disease till the end, but hopefully there will be a surgery real soon, cause I have a younger brother with this, 51 years old, a sister 60 years old left in my family, but 1 brother the oldest in the family, 63 years old he doesn`t have the disease. I`m looking for some good news to lift my spirits for me and my younger brother. Hopefully something will come about on the horizon.
    Thank You So Much,

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