STOCK Fah^1R Tyr^c/RJ

Stock number: 018129
Research areas: Dermatology Research, Developmental Biology Research, Internal/Organ Research, Mouse/Human Gene Homologs, Research Tools

Description

This point mutation provides a model for Type 1 Tyrosinemia, with death occurring within 24 hours of birth.

Detailed description

Fumarylacetoacetate hydrolase is the final enzyme of the tyrosine degradation pathway. This recessive ENU induced point mutation results in neonatal death with all pups dead within 24 hours of birth. These neonates have distinctly elevated succinylacetone in the urine, average 552 ng/ml versus 43 ng/ml in controls. This mutant provides a model for Type 1 Tyrosinemia.

Development

This mutation was made at Oak Ridge National Laboratories by ENU mutagenesis of BALB/cRl males which were then bred to (C57BL/10Rl x C3Hf/Rl)F1 females. The offspring of that cross were bred to a stock bearing Del(Tyr)26DVT, which was generated in (101/Rl x C3H/Rl)F1 then bred through T Stock. How this stock was subsequently maintained prior to crossing to this ENU induced mutant line for mapping is not known. Thus this stock included contributions from several inbreds. At some point the frizzy mutation in coupling with chinchilla were bred into this line and maintained in repulsion with Fah^1R and albino. Sperm was cryopreserved at Oak Ridge National Laboratories from males that were STOCK + Tyr^c-ch Prss8^fr/Fah^1R Tyr^c + . This cryopreserved bankstock was transferred to storage at The Jackson Laboratory in 2009. A successful cryorecovery was performed through assisted in vitro fertilization of B6D2F1 eggs with this thawed sperm. The offspring carrying Fah^1R Tyr^c were then bred to CB6F1 and sperm was cryopreserved from male offspring carrying Fah^1R Tyr^c.

Allele

Symbol: Fah^1R
Name: mutation 1, Oak Ridge
MGI accession ID: MGI:2155424
Generation method: Chemically induced (ENU)
Synonyms: Fah^5961SB; Fah^5981SB; Fah5981SB
Marker symbol: Fah
Marker name: fumarylacetoacetate hydrolase
Marker synonyms: swst
Chromosome: 7
Strain of origin: BALB/cRl
Molecular note: The mutation is a G-to-A transition at the last base of VEGA exon OTTMUSE00000329891 leading to the splicing out of this exon, which results in a frameshift and subsequently the introduction of a premature stop codon at amino acid position 303.

Allele

Symbol: Tyr^c
Name: albino
MGI accession ID: MGI:1855976
Generation method: Spontaneous
Synonyms: c
Marker symbol: Tyr
Marker name: tyrosinase
Marker synonyms: ATN; CMM8; Oca1; OCA1A; OCAIA; SHEP3; skc35
Chromosome: 7
Strain of origin: old mutant of the mouse fancy
Site of expression: Melanocytes.
Molecular note: The specific mutation in the albino allele is a G-to-C transversion causing an amino acid change from cysteine to serine at position 103 or 85 (p.C103S for pre-protein, p.C85S for mature protein). This mutation introduces a DdeI enzyme restriction site.
General note: Tyr^c, albino. This very old mutant was already known in Greek and Roman times. Hair and eyes are completely devoid of pigment (J:5436, J:5001, J:30725). The albino mutation affects the amount of tyrosinase, and thus of melanin, in pigment cells, but does not interfere with the production of pigment cells themselves (J:12173, J:13092). Melanocytes with melanosomes showing normal fine structure occur in the retina and hair follicles. Pigment granules are smaller and fewer than normal and completely lack melanin (J:5346, J:5001, J:30725). Tyrosinase is almost absent (J:12173). Although Tyr is the structural gene for tyrosinase, some albino mutations may affect tyrosinase enzyme regulation rather than structure (J:6611), suggesting that these mutations affect tyrosinase inhibition (J:5346), presumably via control regions of the gene. All the mutant alleles are recessive to wild-type in phenotype, but heterozygotes with wild-type produce intermediate amounts of tyrosinase (J:12173). Albino-locus mutants with lightly pigmented eyes have a reduced number of fibers of the optic nerve going to the ipsilateral lateral geniculate nucleus of the brain. This is probably a secondary effect of reduced tyrosinase activity or amount of pigment in the pigment epithelium, since genes at other loci that reduce eye pigmentation also cause the same anomaly (J:5436, J:6064). Abnormal retinal pathways disrupted at the optic chiasm that occur in albinism can be corrected with a Tyr normal transgene (J:22320). Lipofuscin is a terminal oxidation product pigment that accumulates with age. In a cross of C57BL/6J and BALB/cJ, which differ in cardiac deposition of the pigment, this trait segregated with albinism, and is controlled by the Tyr locus (J:15460). Tyrc homozygotes do not perform as well as normal in a number of behavioral tests. It is likely that this effect is mediated, at least in part, by defective vision resulting from lack of retinal pigment (J:5470, J:5360, J:5378).