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Science 303 (5666): 2033-2036

Copyright © 2004 by the American Association for the Advancement of Science

G Protein-Coupled Receptor-Dependent Development of Human Frontal Cortex

Xianhua Piao,1,2 R. Sean Hill,1 Adria Bodell,1 Bernard S. Chang,1 Lina Basel-Vanagaite,3 Rachel Straussberg,4 William B. Dobyns,5 Bassam Qasrawi,6 Robin M. Winter,7* A. Micheil Innes,8 Thomas Voit,9 M. Elizabeth Ross,10 Jacques L. Michaud,11 Jean-Claude Déscarie,12 A. James Barkovich,13 Christopher A. Walsh1{dagger}

Abstract: The mammalian cerebral cortex is characterized by complex patterns of anatomical and functional areas that differ markedly between species, but the molecular basis for this functional subdivision is largely unknown. Here, we show that mutations in GPR56, which encodes an orphan G protein–coupled receptor (GPCR) with a large extracellular domain, cause a human brain cortical malformation called bilateral frontoparietal polymicrogyria (BFPP). BFPP is characterized by disorganized cortical lamination that is most severe in frontal cortex. Our data suggest that GPCR signaling plays an essential role in regional development of human cerebral cortex.

1 Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, and Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
2 Division of Newborn Medicine, Department of Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3 Department of Medical Genetics, Rabin Medical Center, Petah Tiqva 49100, Israel.
4 Neurogenetics Clinic, Department of Child Neurology, Schneider Children's Medical Center, Petah Tiqva 49202, Israel.
5 Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
6 Social Welfare Institutes, Ministry of Social Affairs and Labor, Kuwait City 13006, Kuwait.
7 Clinical Genetics Unit, Institute of Child Health, London WC1N 1EH, UK.
8 Department of Medical Genetics, University of Calgary, Alberta Children's Hospital, S.W. Calgary, Alberta T2T 5C7, Canada.
9 Department of Pediatrics, University of Essen, 45122 Essen, Germany.
10 Department of Neurology and Neuroscience, Cornell University, New York, NY 10021, USA.
11 Division of Medical Genetics, Hôpital Ste-Justine, Montreal, Quebec H3T 1C5, Canada.
12 Department of Medical Imaging, Hôpital Ste-Justine, Montreal, Quebec H3T 1C5, Canada.
13 Pediatric Neuroradiology, Department of Radiology, University of California, San Francisco, CA 94143 USA.

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* Deceased.

{dagger} To whom correspondence should be addressed. E-mail: cwalsh{at}

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