I received my pediatric training at the Ohio State University and am presently a member of the Department of Metabolism at the Children's Hospital of Philadelphia. While caring for patients with disorders of intermediary metabolism I have developed an interest in the underlying molecular genetic mechanisms of these disorders. I have been actively investigating Glanzmann's thrombasthemia an inborn error of platelet function which is due to absence of the membrane glycoprotein IIb. Specifically I was involved in the isolation of a cDNA clone for this protein and determination of the intron-exon organization it's gene. I am planning on applying my recombinant DNA research skills to other inborn errors of metabolism The initial disorder that I will investigate is galactosemia, and inborn error of galactose metabolism that is the subject of intense investigation in the Department of Metabolism. This autosomal recessive disorder is caused by the absence of activity of the enzyme galactose-1-phosphate uridyl transferase. Complete absence of activity of this enzyme results in the severe disease """"""""classic"""""""" galactosemia. In addition there are a number of clinical variants that have decreased but not absent activity of uridyl transferase. These include the following variants: the Negro, the Duarte, the Indiana, the Chicago, the Los Angeles, the Rennes, and the Munster. While electrophoretic changes in migration have been described for these disorders the causative mutations are unknown. The cDNA for galactose-1-phosphate uridyl transferase has been recently isolated. This clone has been given to us for work described herein. Briefly a genomic library will be screened, using the cDNA positive clones isolated, and the intron-exon organization determined. The polymerase chain reaction will be used to amplify cDNA from patients with classic galactosemia, and the clinical variants, to identify the mutations responsible. The laboratory facilities available at Children's Hospital of Philadelphia to support the above investigation is excellent. Automated instruments described elsewhere in this grant will facilitate analysis of data. Several other laboratories are also engaged in molecular biology research and represent a renewing source of advisory expertise.
| Heidenreich, R A; Mallee, J; Segal, S (1993) Rat galactose-1-phosphate uridyltransferase coding sequence, transcription start site and genomic organization. DNA Seq 3:311-8 |
