Protein Found Essential for Brain Development

Researchers have found that the 14-3-3 epsilon protein, one of a family of ubiquitous phosphoserine/threonine-binding proteins, is required for normal brain development, and when a mutation causes a deficiency of this protein, the result is the serious brain disorder known as lissencephaly.

Lissencephaly, which literally means "smooth brain,” is a rare brain formation disorder characterized by the lack of normal convolutions in the brain and an abnormally small head (microcephaly) caused by defective neuronal migration. Lissencephaly may be associated with other diseases, including isolated lissencephaly sequence, Miller-Dieker syndrome (MDS), and Walker-Warburg syndrome.

LIS1 (which stands for Lissencephaly-1) is a gene that is deleted or mutated on a chromosomal region of chromosome 17 (called 17p13.3) in many children with lissencephaly. LIS1 resides fairly close to the 14-3-3 epsilon gene on this chromosome. Patients with lissencephaly only have deletions of one copy of LIS1, but never 14-3-3 epsilon, while patients with MDS have deletions of both genes on the same chromosome.

In a new study published June 8, 2003, in the online edition of Nature Genetics, investigators at the University of California, San Diego (USA; www.uscd.edu), established a crucial role for 14-3-3 epsilon in neuronal development in sustaining the effects of CDK5 phosphorylation and provided a molecular explanation for the differences in severity of human neuronal migration defects with 17p13.3 deletions.

Senior author Dr. Anthony Wynshaw-Boris explained, "This is the first demonstration in mammals that 14-3-3 epsilon is essential for brain development. We also showed that the gene is always deleted on one chromosome in patients with a rare but severe brain disorder called Miller-Dieker syndrome (MDS). Not only does our study determine a novel function for 14-3-3 epsilon, but it also provides a molecular explanation for why MDS patients have more severe lissencephaly.”



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