X-linked lissencephaly and 'double cortex' are allelic human disorders mapping to Xq22.3-Xq23 associated with arrest of migrating cerebral cortical neurons. We identified a novel 10 kb brain-specific cDNA interrupted by a balanced translocation in an XLIS patient that encodes s novel 40 kDa predicted protein named Doublecortin. Four double cortex/X-linked lissencephaly families and three sporadic double cortex patients show independent doublecortin mutations, at least one of them a de novo mutation. Doublecortin contains a consensus Abl phosphorylation site and other sites of potential phosphorylation. Although Doublecortin does not contain a kinase domain, it is homologous to the amino terminus of a predicted kinase protein, indicating a likely role in signal transduction. Doublecortin, along with the newly characterized mDab1, may define an Abl-dependent pathway regulating neuronal migration.
Bibliographical noteFunding Information:
We are deeply indebted to the patients who participated in these studies and to the clinicians who have supplied patient samples not used directly in this work. We also thank Mark Ross and David Vetrie for providing unpublished physical mapping data; S. Bagrodia for providing the mPAK-3 clone; B. Ji, L. Zheng, and S. Hong for technical assistance; S. Miles for oligonucleotide synthesis; J. Gulcher for advice on making the cosmid library; J. Lai and L. Cantley for help with sequence analysis; and B. Harding for providing the picture in Figure 1 B. K. M. A. was supported by an NRSA postdoctoral fellowship (MH10691) and the Goldenson/Berenberg Fellowship, and J. G. G. was supported by an NSADA fellowship (5K12NS01701–04) from the NINDS. This work was supported by grants from the NINDS (KO8-NS01520 and RO1-NS 32457 to C. A. W., R01-NS35515 to M. E. R. and W. B. D.), by the Human Frontier Science Program (to C. A. W.), and by the Mental Retardation Research Center at Children's Hospital. C. A. W. is a scholar of the Rita Allen Foundation.