Turner syndrome is a common chromosomal disorder associated with short stature, ovarian failure, and a collection of variable anatomical abnormalities including congenital webbed neck, shield chest, and cardiac and renal anomalies. This disorder is most commonly associated with a 45,X karyotype, but is found nearly half of the time in individuals carrying different types of structurally abnormal X chromosome. While a monosomy X karyotype implicates haploinsufficiency for X-linked genes in the pathogenesis of Turner syndrome, the latter karyotypes suggest that a more complex series of effects involving X chromosome inactivation and variable expression of X-linked genes are responsible. This revised project examines two of the most common structural abnormalities of the X chromosome associated with Turner syndrome -- isochromosomes for the X chromosome long arm detected in about 15-20% of patients with typical Turner syndrome and small X-derived centric fragments often associated with mental retardation, growth retardation, and dysmorphic facies. We propose a series of experiments to address the nature of these chromosome abnormalities, their molecular basis, and their phenotypic consequences. The data so obtained should be significant for the understanding of the molecular basis of chromosome abnormalities, for examining centromere structure and behavior, and for elucidating the genetic mechanisms responsible for a major syndrome affecting females throughout life. The specific experimental aims of the proposed research are: 1. to determine the molecular structure and genetic origin of a series of patient-derived isochromosomes for the long arm, i(Xq); 2. to determine the molecular structure of a series of experimentally- derived isochromosomes for the short arm, i(Xq), using a newly developed system to select for formation of such chromosomes in cultured cells; 3. to map and clone breakpoints associated with various classes of isochromosome to test the hypothesis that specific DNA sequences are involved in the molecular formation of the isochromosome; 4. to test the hypothesis that both i(Xq) and i(Xp) isochromosomes that differ in their molecular structure also differ in their mitotic stability by measuring the segregation behavior of monocentric or dicentric isochromosomes in cultured cells; and 5. to identify genes from proximal Xp and Xq and to test the hypothesis that such genes are functionally disomic, due to a failure of X inactivation, in patients with small centric X fragments.
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