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Published Online April 22, 2004
Science DOI: 10.1126/science.1096437

Reports

Submitted on February 4, 2004
Accepted on April 13, 2004

Mutations in a Human ROBO Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis

Joanna C. Jen 1*, Wai-Man Chan 2, Thomas M. Bosley 3, Jijun Wan 1, Janai R. Carr 1, Udo Rüb 4, David Shattuck 1, Georges Salamon 5, Lili C. Kudo 6, Jing Ou 1, Doris D. M. Lin 7, Mustafa A. M. Salih 8, Tülay Kansu 9, Hesham al Dhalaan 10, Zayed al Zayed 11, David B. MacDonald 10, Bent Stigsby 10, Andreas Plaitakis 12, Emmanuel K. Dretakis 13, Irene Gottlob 14, Christina Pieh 15, Elias I. Traboulsi 16, Qing Wang 16, Lejin Wang 16, Caroline Andrews 17, Koki Yamada 17, Joseph L. Demer 18, S. S. Karim 19, Jeffry R. Alger 5, Daniel H. Geschwind 1, Thomas Deller 4, Nancy L. Sicotte 1, Stanley F. Nelson 20, Robert W. Baloh 21, Elizabeth C. Engle 22*

1 Department of Neurology, University of California, Los Angeles, CA 90095, USA.
2 Division of Genetics, Children's Hospital Boston, Boston, MA 02115, USA.
3 Neuro-ophthalmology Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
4 Institute of Clinical Neuroanatomy, J. W. Goethe University, 60590 Frankfurt/M, Germany.
5 Department of Radiology, University of California, Los Angeles, CA 90095, USA.
6 Interdepartmental Program in Neurosciences, University of California, Los Angeles, CA 90095, USA.
7 Department of Radiology and Radiologic Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
8 Department of Pediatrics, King Khalid University Hospital, Riyadh, Saudi Arabia.
9 Neuro-Ophthalmology Unit, Hacettepe University Hospitals, Ankara, Turkey.
10 Neuroscience Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
11 Surgery Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
12 Department of Neurology, University of Crete, Heraklion Crete, Greece.
13 Department of Orthopaedics-Traumatology, University of Crete, Heraklion Crete, Greece.
14 Department of Ophthalmology, Leicester University, Leicester, UK.
15 University Eye Clinic, University of Freiburg, Freiburg, Germany.
16 Cleveland Clinic Foundation, Cleveland, OH, USA.
17 Division of Genetics and Department of Neurology, Children's Hospital Boston, Boston, MA 02115, USA.
18 Department of Neurology and Department of Ophthalmology, University of California, Los Angeles, CA 90095, USA.
19 Department of Ophthalmology, University of California, Los Angeles, CA 90095, USA.
20 Department of Human Genetics, University of California, Los Angeles, CA 90095, USA.
21 Department of Neurology and Department of Surgery, University of California, Los Angeles, CA 90095, USA.
22 Division of Genetics, Department of Neurology, Children's Hospital Boston, and Harvard Medical School, Boston, MA 02115, USA.

* To whom correspondence should be addressed.
Joanna C. Jen , E-mail: jjen{at}ucla.edu
Elizabeth C. Engle , E-mail: engle{at}enders.tch.harvard.edu

The mechanisms controlling axon guidance are of fundamental importance in understanding brain development. Growing corticospinal and somatosensory axons cross the midline in the medulla to reach their targets and thus form the basis of contralateral motor control and sensory input. The motor and sensory projections appeared uncrossed in patients with horizontal gaze palsy with progressive scoliosis (HGPPS). In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. Like its murine homolog rig1/robo3, but unlike other robo proteins, ROBO3 is required for hindbrain axon midline crossing.


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