Abstract

The Lesch-Nyhan (L-N) syndrome is an X-linked recessively inherited disease characterized by mental retardation, chorioathetosis, self-mutilative behavior and hyperuricemia. The disorder is genetically lethal, and since the affected males do not reproduce, it arises frequently by new mutation. We propose to study the molecular basis of new mutation in man by examining the types of mutation as well as the paternal gametic origin. The basis of the high level of hypoxanthine-guanine phosphoriboro-syltransferase (HPRT) expression is the central nervous system and the effect of its deficiency state (HPRT-) on neural development is unresolved. We propose to study both cell culture and transgenic mice in an effort to develop a model for L-N pathophysiologic studies. Finally, an attempt to develop HPRT- mice which correspond to the L-N disease of man will be made towards the objective of a model animal system for study and correction of the disease in man.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031428-06
Application #
3230087
Study Section
Neurology C Study Section (NEUC)
Project Start
1982-07-01
Project End
1988-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
6
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Shumaker, J M; Metspalu, A; Caskey, C T (1996) Mutation detection by solid phase primer extension. Hum Mutat 7:346-54
Alford, R L; Redman, J B; O'Brien, W E et al. (1995) Lesch-Nyhan syndrome: carrier and prenatal diagnosis. Prenat Diagn 15:329-38
Wu, X W; Muzny, D M; Lee, C C et al. (1992) Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 34:78-84
Huang, T H; Hejtmancik, J F; Edwards, A et al. (1991) Linkage of the gene for an X-linked mental retardation disorder to a hypervariable (AGAT)n repeat motif within the human hypoxanthine phosphoribosyltransferase (HPRT) locus (Xq26). Am J Hum Genet 49:1312-9
Rossiter, B J; Fuscoe, J C; Muzny, D M et al. (1991) The Chinese hamster HPRT gene: restriction map, sequence analysis, and multiplex PCR deletion screen. Genomics 9:247-56
Gibbs, R A; Nguyen, P N; Edwards, A et al. (1990) Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families. Genomics 7:235-44
Munir, M I; Rossiter, B J; Caskey, C T (1990) Antisense RNA production in transgenic mice. Somat Cell Mol Genet 16:383-94
Edwards, A; Voss, H; Rice, P et al. (1990) Automated DNA sequencing of the human HPRT locus. Genomics 6:593-608
Rossiter, B J; Muzny, D M; Hampson, I et al. (1990) Induced reversion of a spontaneous point mutation within the Chinese hamster HPRT gene to the wild-type sequence. Mutagenesis 5:605-8
Gibbs, R A; Nguyen, P N; McBride, L J et al. (1989) Identification of mutations leading to the Lesch-Nyhan syndrome by automated direct DNA sequencing of in vitro amplified cDNA. Proc Natl Acad Sci U S A 86:1919-23

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