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Got Milk? Utah Scientists Discover Key Lactation Gene Mutant Version May Explain Why Some Women Have Trouble Breast-Feeding

The embargoed news release below was issued by Cold Spring Harbor Laboratory Press in Cold Spring Harbor, N.Y., publisher of the journal Genes & Development. It outlines a study by University of Utah geneticist Mario Capecchi and colleagues discovering one of many genes involved in milk production by female mice and possibly by human females as well. The original release has been modified by the addition of contact information and titles for the authors and some other details.

December 14, 2002 — Geneticist Mario Capecchi and colleagues at the University of Utah and the Department of Veterans Affairs Medical Center in Salt Lake City, Utah, have discovered that a gene called xanthine oxidoreductase, or XOR for short, is required for lactation in female mice. This previously unidentified role for XOR in lactation reveals a possible genetic basis for the lactation difficulties experienced by nearly 5 percent of women.

The new study will appear in the Dec. 15 issue of the journal Genes & Development.

The XOR gene 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 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, 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 six 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 about 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 and Capecchi 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.

Vorbach emphasized that XOR is only one of many genes involved in lactation.

This discovery that two 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.

Capecchi is co-chair of the University of Utah Department of Human Genetics and is a distinguished professor of genetics and biology. Vorbach is a research associate in genetics. The third co-author of the study is physician Alistair Scriven, an assistant professor of internal medicine at the university. He bred the mice used in the study.