Aicardi and Goltz syndromes are both X-linked dominant disorders with lethality in males. We have collected cell lines from a number of patients with chromosomal rearrangements showing clinical features of Aicardi syndrome, Goltz syndrome, or both. These patents suffer from a combination of clinical features and developmental defects which include agenesis of the corpus callosum, seizures, developmental delay, retinal lesions, microphthalmia and skin defects. The phenotypes of these patients show significant overlap, suggesting that the same gene, or two or more contiguous genes, may be involved. The variability of the phenotype may be due to the effects of X-inactivation. In all these cases the chromosomal rearrangement results in a terminal deletion involving the Xp22.2-Xp22.3 region, strongly suggesting that the loci for Aicardi and Goltz syndromes map to this region. Therefore: these cell lines represent ideal tools to perform positional cloning of the genes which are mutated in Aicardi and Goltz syndromes. Somatic cell hybrids from these cell lines will be established in order to separate the abnormal X chromosome from the normal one. Precise mapping of the Aicardi and Goltz syndrome critical regions will be obtained by testing the hybrid cell lines with numerous existing and newly generated markers from Xp22.2Xp22.3. We will then perform overlap cloning using yeast artificial chromosome (YAC) clones obtained from several libraries, including a library specifically made from a hybrid retaining the human Xp2l-pter region. YAC subclones will be used for the identification of genes from the region. The expression pattern and sequence analysis of the genes will be examined in normal individuals and in patients affected by Aicardi and Goltz syndromes to determine their involvement in the pathogenesis of these diseases. Further studies will include the characterization of the structure and function of the disease genes and of their products.
Showing the most recent 10 out of 11 publications
