In vivo suppressor mutations correct a murine model of hereditary tyrosinemia type I

Kara Manning, Muhsen Al-Dhalimy, Milton Finegold, Markus Grompe

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Hereditary tyrosinemia type I and alkaptonuria are disorders of tyrosine catabolism caused by deficiency of fumarylacetoacetate hydrolase (FAH) and homogentisic acid dioxygenase (HGD), respectively. Tyrosinemia is a severe childhood disease that affects the liver and kidneys, but alkaptonuria is a more benign adult disorder in comparison. Because HGD is upstream of FAH in the tyrosine pathway, mice doubly mutant in both enzymes were found to be protected from the liver and renal damage of tyrosinemia as hypothesized. Mice mutant at the tyrosinemic locus but heterozygous for alkaptonuria spontaneously developed clonal nodules of functionally normal hepatocytes that were able to rescue the livers of some mice with this genotype. This phenotypic rescue was a result of an inactivating mutation of the wild-type homogentisic acid dioxygenase gene, thus presenting an example of an in vivo suppressor mutation in a mammalian model.

Original languageEnglish (US)
Pages (from-to)11928-11933
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number21
DOIs
StatePublished - Oct 12 1999

ASJC Scopus subject areas

  • General

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