Previously, the PI's laboratory identified the LIS1 gene as the gene for lissencephaly in Miller-Dieker syndrome (MDS) and isolated lissencephaly sequence (ILS17). Hemizygous deletions or mutations in LIS1 confirmed that lissencephaly is due to haploinsufficiency of the protein product beta LIS1. The identification of LIS1 allows testing of several hypotheses related to the mechanisms of mutations as well as the protein's functional role in normal human brain development. These hypotheses include: i) Chromosome-specific repeats mediate the deletions in MDS/ILS17, as recently observed in other microdeletion syndromes. ii) Additional genes in the region telomeric to LIS1 have important roles in brain development, accounting for the more severe brain malformations in MDS. iii) Beta LIS1 has a cell autonomous function, and mutations or deletion of the gene affect only the cells carrying the mutation. Mosaicism via somatic mutations produces subcortical band heterotopia/double cortex (SBHDC). iv) Proteins that interact with beta LIS1, that participate in the same pathway, or that have similar functions, are responsible for other forms of lissencephaly. These hypotheses will be tested in 3 specific aims.
Specific aim 1. Development of a high resolution physical map and transcript map of the MDS chromosome region in 17p13.3 to identify and clone 'hotspots' for chromosome breakage as well as additional genes involved in brain development.
Specific aim 2. Determine the frequency and pattern of mutations in LIS1 in a large series of ILS17 patients, allowing inferences about important functional domains in beta LIS1. Rare males and females with SBHDC will be tested for mosaic deletions or mutations.
Specific aim 3. Identify additional autosomal lissencephaly genes using a candidate gene and positional candidate approach. Strong candidate genes include those with high sequence homology or similar function to LIS1 or DBCN, those genes whose protein products interact with or are part of the same biochemical pathway, and genes identified as having an important neuronal migration phenotype in mouse mutants or knockouts. FISH or mutation analysis will be used to examine candidate genes in lissencephaly patients without deletion or mutation of LIS1 or DBCN.
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