B6.129(Cg)-Slc25a13^tm1Lct/TsahMmjax

Stock number: 036925
Product name: Ctrn^-
Research areas: Diabetes and Obesity Research, Metabolism Research

Description

Ctrn^-/- knockout mice have exon 10 replaced by a neomycin cassette in the Slc25a13 (solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 13 or Ctrn) gene. Homozygous null mice exhibit hypoglycemia, decreased insulin levels and increased liver triglycerides, as well as defects in ureogenesis and gluconeogenesis. This strain maybe of interest in studies of human citrin deficiency.

Detailed description

Slc25a13 (solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator or citrin/Ctrn) encodes a member of the mitochondrial carrier family that catalyzes the exchange of mitochondrial aspartate for cytoplasmic glutamate and a proton across the inner mitochondrial membrane. Mutations in SLC25A13 are associated with age-specific clinical presentations including neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset type II citrullinemia (CTLN2), a disease characterized by a liver-specific decrease of argininocuccinate synthetase (ASS) resulting in citrullinemia and hyperammonemia as well neuropsychiatric symptoms.

Ctrn^-/- KO mice have exon 10 replaced by a neomycin cassette resulting in a null allele. Mice heterozygous for the mutation are viable and fertile. Biochemical analysis of liver mitochondria isolated from homozygous mice reveals a decrease in Asp formation and a reduction in Mal-Asp shuttle activity. Lactate perfusion of homozygous liver results in a reduced ability to produce glucose, and an increase in the lactate to pyruvate (L/P) ratio, and NH₄Cl liver perfusion results in a decrease in urea production. In addition, Ctrn^-/- mice exhibit hypoglycemia under fasting and fed conditions, as well decreased insulin levels (fed) and increased liver triglcyerides.

When combined with mice carrying a null allele of mGPDH, double mutant mice develop citrullinemia, hyperammonemia, hypoglycemia and fatty liver and maybe be used as a mouse model of human citrin deficiency.

Of note, the Ctrn KO is also available on the BALB background, C.129-Slc25a13^tm1Lct/Mmjax MMRRC Stock No. 069594.

Development

Ctrn^- mice were created by Dr. David S Sinasac (University of Toronto). The targeting vector was designed to replace a 347 bp region containing exon 10 with a PGK-neomycin cassette (in the opposite orientation) in the Slc25a13 gene on chromosome 6. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and the resulting chimeric males from this line were bred with CD1 females. Western blot analysis confirmed the absence of citrin protein in kidney, liver and heart. Mice from the colony were transferred into the laboratory of Dr. Takeyori Saheki (Kagoshima University) and were bred to C57BL/6J mice for at least 9 generations. C57BL/6 congenic mGPDH^- mice were crossed to Ctrn^- mice to generate the double knock-out. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation. The mGDPH (Gpd2^tm1Tka) allele was bred out of this strain.

Allele

Symbol: Slc25a13^tm1Lct
Name: targeted mutation 1, Lap-Chee Tsui
MGI accession ID: MGI:3028639
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: Ctrn ^-/-
Marker symbol: Slc25a13
Marker name: solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 13
Marker synonyms: ARALAR2; citrin; CTLN2; Ctrn; NICCD; RGD1565889
Chromosome: 6
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Molecular note: A 347 bp region containing exon 10 was replaced with a neomycin resistance gene inserted in opposite orientation. Absence of mRNA transcript was confirmed by Northern blot and absence of protein product by Western blot analysis.