Poirier et al. (2013) reported 4 brothers with severe malformations of cortical development. The proband showed intrauterine growth retardation, severe arthrogryposis, and microcephaly (-4 SD) at birth, and developed clonic seizures in the first months of life. Brain ... Poirier et al. (2013) reported 4 brothers with severe malformations of cortical development. The proband showed intrauterine growth retardation, severe arthrogryposis, and microcephaly (-4 SD) at birth, and developed clonic seizures in the first months of life. Brain MRI showed frontal and perisylvian polymicrogyria and a thin corpus callosum with a normal brainstem and cerebellar vermis. The infant was bedridden with spastic tetraplegia. The unaffected mother subsequently had 3 medical abortions of similarly affected male fetuses who showed fetal akinesia associated with polymicrogyria, gyral simplification, delayed development of the cerebellum and brainstem, and abnormal positioning of the corticospinal tracts.
In 4 brothers with complex cortical dysplasia with other brain malformations-2, Poirier et al. (2013) identified a heterozygous mutation in the KIF5C gene (E237V; 604593.0001). The mutation was identified by whole-exome sequencing and was not found in several ... In 4 brothers with complex cortical dysplasia with other brain malformations-2, Poirier et al. (2013) identified a heterozygous mutation in the KIF5C gene (E237V; 604593.0001). The mutation was identified by whole-exome sequencing and was not found in several genomic databases, including dbSNP, 1000 Genomes, Exome Variant Server, and a local Paris Descartes Bioinformatics platform database. The unaffected mother was determined to be germline mosaic for the mutation. In vitro functional expression studies in E. coli and COS-7 cells showed that the mutant protein had a complete loss of ATP hydrolysis activity. In COS-7 cells, mutant KIF5C heavily colocalized with microtubules throughout the cell, but did not appear as puncta or accumulate in cortical clusters as did the wildtype protein. Poirier et al. (2013) postulated a dominant-negative effect. The findings extended the association between microtubule-based cellular processes and proper cortical development.