ELUCIDATION OF DYSMYELINATION IN THE 18Q-SYNDROME

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DESCRIPTION (adapted from applicant's abstract): Dysmyelination of the central nervous system is a key feature in individuals with the 18q- syndrome, a syndrome that results from loss of chromosomal material from the long arm of chromosome 18. Other common findings in 18q- patients include mental retardation, developmental delay, and hearing impairment. Through the studies of over 40 patients with this syndrome, the investigators have established that the most common feature of this syndrome is dysmyelination. From molecular genetic experiments, they have identified a region on chromosome 18 that is missing in each patient with dysmyelination. This region is therefore the "critical region" for dysmyelination in this syndrome. The gene that codes for myelin basic protein (MBP) maps into this critical region on chromosome 18q. However, mouse models have demonstrated that loss of one copy of the MBP gene is not sufficient to cause dysmyelination in the mouse. Since the 18q- syndrome is a contiguous gene syndrome, they hypothesize that there is more than one gene that must be lost from this region in humans and mice to have dysmyelination. Thus to test this hypothesis, they propose to make a mouse model that is missing the region of the mouse genome that is homologous to the "critical region" they identified in their human studies. To construct this mouse model, they propose three specific aims. The first aim is to map the transcripts they have identified in the human critical region into the mouse genome. The second aim will be to develop a mouse model with a deletion of the "critical region" using the Cre/loxP system. The third aim will be to characterize the myelin in this mouse model using molecular, structural and functional assays. These experiments will help them gain insight into the mechanism of abnormal myelination in patients with 1 8qsyndrome. In addition, this mouse model will be an important tool for future studies that focus on identifying genes that affect patients with 18q- syndrome. The information from these studies could ultimately lead to therapeutic intervention for this disorder.