Characterization of mutations in the gene doublecortin in patients with double cortex syndrome

Mutations in the X-linked gene doublecortin, which encodes a protein with n o clear structural homologues, are found in pedigrees in which affected fem ales show "double cortex" syndrome (DC; also known as subcortical band hete rotopia or laminar heterotopia) and affected males show X-linked lissenceph aly. Mutations in doublecortin also cause sporadic DC in females. To determ ine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the d oublecortin open reading frame as assessed by single-stranded conformationa l polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identifie d mutations were of two types, protein truncation mutations and single amin o acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patie nts with these mutations may have less of a reproductive disadvantage versu s those patients with protein truncation mutations. Single amino acid subst itution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein.