XOR was originally identified as encoding an enzyme involved in purine catabolism (the breakdown of adenine and guanine nucleotide bases). Because XOR is expressed in nearly all cells of the body and its protein product participates in a basic metabolic process fundamental to cell survival, XOR was labeled as a "housekeeping gene." But in addition to its constitutive expression patterns, XOR is also highly expressed in lactating mammary epithelium beginning in late pregnancy - prompting researchers to suspect an additional, and perhaps different, role for XOR in the lactating mammary gland.
To identify the function of XOR in the lactating mammary gland, Dr. Capecchi and colleagues generated mice lacking either one (heterozygous) or both (homozygous) functional copies of the XOR gene. As expected for homozygous mutants of a housekeeping gene, homozygous XOR-mutant mice died by 6 weeks of age. In contrast, though, the heterozygous XOR-mutant mice appeared normal, healthy and fertile, but first author Claudia Vorbach and colleagues soon noticed that pups from the XOR heterozygous females all died ~12 days postpartum. The researchers found that pups born to heterozygous XOR-mutant female mice - regardless of the pups' XOR status - were essentially starving due to their mother's inability to maintain lactation.
Further research by Vorbach et al. revealed an important role for the XOR protein in lactation, distinct from its previously identified role in purine catabolism. XOR is required for the envelopment of milk fat droplets with a phospholipid bilayer that is necessary for their secretion from the mammary epithelium. The inability of heterozygous XOR-mutant females to secrete milk fat droplets causes severe tissue damage, resulting in the collapse of the mammary epithelium and the subsequent premature involution of the mammary gland.
This discovery that 2 functional copies of the XOR gene are necessary for females to secrete fat - the major calorie supply for newborns - into milk not only broadens the known functional range of XOR, it lends important molecular insight into the process of lactation, and suggests that human females with mutations in the XOR gene may be potential candidates for lactation insufficiencies.