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Originally published in Science Express on 22 April 2004
Science 4 June 2004:
Vol. 304. no. 5676, pp. 1509 - 1513
DOI: 10.1126/science.1096437
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Reports

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

Joanna C. Jen,1* Wai-Man Chan,7 Thomas M. Bosley,10 Jijun Wan,1 Janai R. Carr,1 Udo Rüb,11 David Shattuck,1 Georges Salamon,2 Lili C. Kudo,3 Jing Ou,1 Doris D. M. Lin,12 Mustafa A. M. Salih,13 Tülay Kansu,14 Hesham al Dhalaan,15 Zayed al Zayed,16 David B. MacDonald,15 Bent Stigsby,15 Andreas Plaitakis,17 Emmanuel K. Dretakis,18 Irene Gottlob,19 Christina Pieh,20 Elias I. Traboulsi,21 Qing Wang,21 Lejin Wang,21{dagger} Caroline Andrews,7,9 Koki Yamada,7,9 Joseph L. Demer,1,4 Shaheen Karim,4 Jeffry R. Alger,2 Daniel H. Geschwind,1 Thomas Deller,11 Nancy L. Sicotte,1 Stanley F. Nelson,5 Robert W. Baloh,1,6 Elizabeth C. Engle7,8,9*

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.

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



{dagger} Present address: Laboratory of Molecular Ophthalmic Genetics, Department of Pediatric Ophthalmology and Strabismus, Peking University Eye Center, Peking University No. 3 Hospital.

* To whom correspondence should be addressed. E-mail: jjen{at}ucla.edu (J.C.J.); engle{at}enders.tch.harvard.edu (E.C.E.)

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