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Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22229-22236. doi: 10.1073/pnas.1904485116. Epub 2019 Oct 14.

Tissue-specific FAH deficiency alters sleep-wake patterns and results in chronic tyrosinemia in mice.

Author information

1
Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111.
2
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111.
3
Department of Neurobiology, Northwestern University, Evanston, IL 60208.
4
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111; joseph.takahashi@utsouthwestern.edu.

Abstract

Fumarylacetoacetate hydrolase (FAH) is the last enzyme in tyrosine catabolism, and mutations in the FAH gene are associated with hereditary tyrosinemia type I (HT1 or TYRSN1) in humans. In a behavioral screen of N-ethyl-N-nitrosourea mutagenized mice we identified a mutant line which we named "swingshift" (swst, MGI:3611216) with a nonsynonymous point mutation (N68S) in Fah that caused age-dependent disruption of sleep-wake patterns. Mice homozygous for the mutation had an earlier onset of activity (several hours before lights off) and a reduction in total activity and body weight when compared with wild-type or heterozygous mice. Despite abnormal behavioral entrainment to light-dark cycles, there were no differences in the period or phase of the central clock in mutant mice, indicating a defect downstream of the suprachiasmatic nucleus. Interestingly, these behavioral phenotypes became milder as the mice grew older and were completely rescued by the administration of NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione], an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, which is upstream of FAH. Mechanistically, the swst mutation had no effect on the enzymatic activity of FAH, but rather promoted the degradation of the mutant protein. This led to reduced FAH protein levels and enzymatic activity in the liver and kidney (but not the brain or fibroblasts) of homozygous mice. In addition, plasma tyrosine-but not methionine, phenylalanine, or succinylacetone-increased in homozygous mice, suggesting that swst mutants provide a model of mild, chronic HT1.

KEYWORDS:

ENU mutagenesis; sleep; tyrosinemia

PMID:
31611405
PMCID:
PMC6825319
[Available on 2020-04-14]
DOI:
10.1073/pnas.1904485116

Conflict of interest statement

The authors declare no competing interest.

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