doublecortin, a Brain-Specific Gene Mutated in Human X-Linked Lissencephaly and Double Cortex Syndrome, Encodes a Putative Signaling Protein

Abstract

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 a 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.

LIS1—no more no less

“…41 Mutations in two different genes may result in type I lissencephaly: LIS1, 4 and doublecortin, an X-linked gene. 2,3 The phenotypic presentation of the patients is very similar. However, while the frontal brain is more affected in patients with mutated doublecortin, LIS1 mutations affect mainly the parietal and occipital cortex.…”

Cycling, stressed-out and nervous: cellular functions of c-Abl

“…The scrambler gene encodes the murine homologue of Disabled (mDab1) 54 that, like its Drosophila counterpart, is a tyrosine-phosphorylated PTB-containing adaptor protein expressed in developing cortical neurons. Human patients with recessive X-linked lissencephaly/double cortex syndrome, characterized by defective migration of a population of cortical neurons leading to migrational arrest in the subcortical white matter, have mutations in Doublecortin, a novel brain-specific signalling protein with potential Abl phosphorylation sites 55 .…”

Ectopic Doublecortin Gene Expression Suppresses the Malignant Phenotype in Glioblastoma Cells

“…Doublecortex is also known as doublecortin (DCX), a microtubule binding protein with two actin-binding domains that regulate neuronal migration and located on chromosome Xq22.3-q23 (7)(8)(9)(10)(11). Mutations in the X-linked DCX gene result in lissencephaly, which is a severe brain disorder in newborns and is a result of abnormal neuronal migration (12).…”