Journal Article

Doublecortin mutations cluster in evolutionarily conserved functional domains

Tamar Sapir, David Horesh, Michal Caspi, Roee Atlas, Harold A. Burgess, Sharon Grayer Wolf, Fiona Francis, Jamel Chelly, Michael Elbaum, Shmuel Pietrokovski and Orly Reiner

in Human Molecular Genetics

Volume 9, issue 5, pages 703-712
Published in print March 2000 | ISSN: 0964-6906
Published online March 2000 | e-ISSN: 1460-2083 | DOI:
Doublecortin mutations cluster in evolutionarily conserved functional domains

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Mutations in the X-linked gene doublecortin (DCX) result in lissencephaly in males or subcortical laminar heterotopia (‘double cortex’) in females. Various types of mutation were identified and the sequence differences included nonsense, splice site and missense mutations throughout the gene. Recently, we and others have demonstrated that DCX interacts and stabilizes microtubules. Here, we performed a detailed sequence analysis of DCX and DCX-like proteins from various organisms and defined an evolutionarily conserved Doublecortin (DC) domain. The domain typically appears in the N-terminus of proteins and consists of two tandemly repeated 80 amino acid regions. In the large majority of patients, missense mutations in DCX fall within the conserved regions. We hypothesized that these repeats may be important for microtubule binding. We expressed DCX or DCLK (KIAA0369) repeats in vitro and in vivo. Our results suggest that the first repeat binds tubulin but not microtubules and enhances microtubule polymerization. To study the functional consequences of DCX mutations, we overexpressed seven of the reported mutations in COS7 cells and examined their effect on the microtubule cytoskeleton. The results demonstrate that some of the mutations disrupt microtubules. The most severe effect was observed with a tyrosine to histidine mutation at amino acid 125 (Y125H). Produced as a recombinant protein, this mutation disrupts microtubules in vitro at high molar concentration. The positions of the different mutations are discussed according to the evolutionarily defined DC-repeat motif. The results from this study emphasize the importance of DCX–microtubule interaction during normal and abnormal brain development.

Journal Article.  7555 words.  Illustrated.

Subjects: Genetics and Genomics

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