Uniparental disomy (UPD) is the abnormal inheritance of both copies of chromosome from the same parent with no contribution of that particular chromosome from the other parent. UPD has been described for many human chromosomes, resulting in varying clinical outcomes. An abnormal phenotype may result from genes on a chromosome that are subject to genomic imprinting. Genomic imprinting is the molecular mechanism by which there can be differential expression of genes from either the maternally-or paternally inherited chromosome. The clinical description of cases with either maternal and paternal disomy 14 has enable the characterization of distinct syndromes for each. Individuals with paternal disomy 14 present with a more several phenotype with includes mental retardation, skeletal abnormalities that result in a short- limb dwarfism with narrow thorax, decreased survival due to respiratory difficulties, dysmorphic facies, scoliosis, and short status. This application proposes to identify imprinted genes on human chromosome 14 through two Specific Aims. First, differentially expressed sequences will be identified from maternally- and paternally-derived chromosomes 14. Expressed sequences from cell lines of either maternal disomy 14 or paternal disomy 14 will be compared through direct analysis of known genes, hybridization to arrayed cDNA filters, and suppression subtraction hybridization to identify imprinted genes. Second, differentially expressed sequences will be characterized in order to understand the molecular mechanism of genomic imprinting and the effects of phenotype. The differentially expressed sequences will be sequenced and full length cDNAs will be identified. Sequences will be analyzed for parent-specific methylation and expression to begin to understand the molecular elements used to control the imprinting process. The identification of genes that are subject to genomic imprinting will allow insight into the mechanisms of genomic imprinting in normal and abnormal human development and mental retardation syndromes and may lead to further advances in the diagnosis and molecular understanding of UPD disorders.
