MOLECULAR GENETIC ANALYSIS OF THE PRADER-WILLI SYNDROME LOCUS

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Prader-Willi syndrome (PWS) is a genetic disease characterized by mental retardation, obesity and hypogonadism. The majority of patients display a characteristic deletion of chromosome 15q11q13. This deletion is always of paternal origin. In cases where there is no detectable deletion, uniparental maternal disomy of chromosome 15q is observed. These findings indicate that the PWS disease locus is genetically imprinted. We propose to more narrowly delineate the PWS critical region of deletion overlap by identifying and cloning the breakpoint junction of an unbalanced translocation associated with PWS. Cosmid and lambda phage libraries constructed from flow sorted chromosome 15q11q13 material as well as yeast artificial chromosome clones will be used to clone the breakpoint junction. These reagents will also be used to construct a contig of the PWS critical region. Potential transcription units in the PWS critical region will then be identified. We will determine whether any of the transcribed sequences which map to the PWS critical region display allele-specific expression. This will be accomplished using a PCR-based assay for short tandem repeats which occur in the 3' untranslated regions of the cDNAs from the PWS critical region. A gene from the PWS critical region which is expressed exclusively from the paternal chromosome 15 will be classified as a candidate gene for PWS.