Mitochondrial complex I (CI)-associated defects are the most common mitochondrial disorders. Defects in the non-enzymatic, nuclear-encoded CI protein NDUFS4 (NADH dehydrogenase (ubiquinone) Fe-S protein 4) cause a Leigh-like phenotype in humans that results in death within 3–16 months after birth.
Exon 2 of the mouse Ndufs4 gene has been excised in this knockout allele. Homozygous knockout mice are smaller than normal and begin losing body hair by postnatal day 21 (P21). Hair grows back during the next hair-growth cycle. Animals have normal locomotor activity during both day and night until approximately P30, after which they become lethargic. Knockout mice are blind and cataracts sometimes appear in one or both eyes as early as P20. After P35, some knockout mice are unable to open their eyes completely and, with variable time of onset, there is a rapid decline in acoustic startle response. Starting around P35, the homozygous knockout mice develop severe ataxia. Between P35 and P50, the knockout mice stop gaining weight, display worsened ataxia, cease grooming, and die. Homozygous knockout mice die by P55 and are infertile; heterozygotes appear normal for at least a year.
Exon 2, encoding the last part of a mitochondrial targeting sequence and the first 17 amino acids of the mature protein, was flanked by loxP sites and an FRT-flanked SV-Neo cassette was introduced to intron 5 using 129S4/SvJaeSor-derived AK18.1 embryonic stem (ES) cells. Resultant mice were crossed with Gt(ROSA)26Sor-FLPo mice (see Stock No. 007844) to excise the neo cassette. Exon 2 was deleted via crosses with germline-specific Meox2-cre; see Stock No. 003755). The line was backcrossed to C57BL/6J for more than 20 generations by the donating lab.
|Allele Name||targeted mutation 1.1, Richard D Palmiter|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||Ndufs4 KO; Ndufs4delta|
|Gene Symbol and Name||Ndufs4, NADH:ubiquinone oxidoreductase core subunit S4|
|Strain of Origin||129S4/SvJaeSor|
|Molecular Note||Germ line, cre mediated recombination was used to remove exon 2, which contains the mitochondrial targeting sequence. The absence of protein product was confirmed by western blot analysis.|
Heterozygous mice are viable and fertile. Homozygous knockout mice die by postnatal day 55 and are infertile.
When using the B6.129S4-Ndufs4tm1.1Rpa/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #027058 in your Materials and Methods section.