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.
