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

Shuzhang Yang, Sandra M. Siepka, Kimberly H. Cox, Vivek Kumar, Marleen De Groot, Yogarany Chelliah, Jun Chen, Benjamin Tu, Joseph S. Takahashi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)22229-22236
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number44
DOIs
StatePublished - Oct 29 2019

Fingerprint

Tyrosinemias
Sleep
Mutation
Tyrosine
4-Hydroxyphenylpyruvate Dioxygenase
Ethylnitrosourea
Suprachiasmatic Nucleus
Photoperiod
Mutant Proteins
fumarylacetoacetase
Phenylalanine
Point Mutation
Methionine
Fibroblasts
Body Weight
Phenotype
Kidney
Light
Liver
Brain

Keywords

  • ENU mutagenesis
  • Sleep
  • Tyrosinemia

ASJC Scopus subject areas

  • General

Cite this

Tissue-specific FAH deficiency alters sleep-wake patterns and results in chronic tyrosinemia in mice. / Yang, Shuzhang; Siepka, Sandra M.; Cox, Kimberly H.; Kumar, Vivek; De Groot, Marleen; Chelliah, Yogarany; Chen, Jun; Tu, Benjamin; Takahashi, Joseph S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 44, 29.10.2019, p. 22229-22236.

Research output: Contribution to journalArticle

Yang, Shuzhang ; Siepka, Sandra M. ; Cox, Kimberly H. ; Kumar, Vivek ; De Groot, Marleen ; Chelliah, Yogarany ; Chen, Jun ; Tu, Benjamin ; Takahashi, Joseph S. / Tissue-specific FAH deficiency alters sleep-wake patterns and results in chronic tyrosinemia in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 44. pp. 22229-22236.
@article{21b6a93ee22f4e5a892e747c88358628,
title = "Tissue-specific FAH deficiency alters sleep-wake patterns and results in chronic tyrosinemia in mice",
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",
author = "Shuzhang Yang and Siepka, {Sandra M.} and Cox, {Kimberly H.} and Vivek Kumar and {De Groot}, Marleen and Yogarany Chelliah and Jun Chen and Benjamin Tu and Takahashi, {Joseph S.}",
year = "2019",
month = "10",
day = "29",
doi = "10.1073/pnas.1904485116",
language = "English (US)",
volume = "116",
pages = "22229--22236",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "44",

}

TY - JOUR

T1 - Tissue-specific FAH deficiency alters sleep-wake patterns and results in chronic tyrosinemia in mice

AU - Yang, Shuzhang

AU - Siepka, Sandra M.

AU - Cox, Kimberly H.

AU - Kumar, Vivek

AU - De Groot, Marleen

AU - Chelliah, Yogarany

AU - Chen, Jun

AU - Tu, Benjamin

AU - Takahashi, Joseph S.

PY - 2019/10/29

Y1 - 2019/10/29

N2 - 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.

AB - 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.

KW - ENU mutagenesis

KW - Sleep

KW - Tyrosinemia

UR - http://www.scopus.com/inward/record.url?scp=85074187097&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074187097&partnerID=8YFLogxK

U2 - 10.1073/pnas.1904485116

DO - 10.1073/pnas.1904485116

M3 - Article

C2 - 31611405

AN - SCOPUS:85074187097

VL - 116

SP - 22229

EP - 22236

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 44

ER -