LACTATION IS DISRUPTED BY ALPHA-LACTALBUMIN DEFICIENCY AND CAN BE RESTORED BY HUMAN ALPHA-LACTALBUMIN GENE REPLACEMENT IN MICE

Mice carrying either a deletion of the murine alpha-lactalbumin (alpha -lac) gene (null allele) or its replacement by the human alpha-lac gen e (humanized allele) have been generated by gene targeting. Homozygous null females are alpha-lac-deficient, produce reduced amounts of thic kened milk containing little or no lactose, and cannot sustain their o ffspring. This provides definitive evidence that alpha-lac is required for lactose synthesis and that lactose is important for milk producti on, Females homozygous for the humanized allele lactate normally, indi cating that human alpha-lac can replace murine alpha-lac. Mouse and hu man alpha-lac expression was compared in mice heterozygous for the hum anized allele. The human gene expressed approximate to 15-fold greater mRNA and approximate to 14-fold greater protein than the mouse, indic ating that the major determinants of human alpha-lac expression are cl ose to, or within, the human gene and that the mouse locus does not ex ert 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 homo zygous for the humanized allele. These variations demonstrated that al pha-lac expression in mice is gene dosage dependent.