Abstract
Mice carrying either a deletion of the murine alpha-lactalbumin (alpha-lac) gene (null allele) or its replacement by the human alpha-lac gene (humanized allele) have been generated by gene targeting. Homozygous null females are alpha-lac-deficient, produce reduced amounts of thickened milk containing little or no lactose, and cannot sustain their offspring. This provides definitive evidence that alpha-lac is required for lactose synthesis and that lactose is important for milk production. Females homozygous for the humanized allele lactate normally, indicating that human alpha-lac can replace murine alpha-lac. Mouse and human alpha-lac expression was compared in mice heterozygous for the humanized allele. The human gene expressed approximately 15-fold greater mRNA and approximately 14-fold greater protein than the mouse, indicating that the major determinants of human alpha-lac expression are close to, or within, the human gene and that the mouse locus does not exert a negative influence on alpha-lac expression. Variations in alpha-lac expression levels in nondeficient mice did not affect milk lactose concentration, but the volume of milk increased slightly in mice homozygous for the humanized allele. These variations demonstrated that alpha-lac expression in mice is gene dosage dependent.