Lactase - Genetic Expression and Regulation

Genetic Expression and Regulation

Lactase is encoded by a single genetic locus on chromosome 2. It is expressed exclusively by mammalian small intestine enterocytes and in very low levels in the colon during fetal development. Humans are born with high levels of lactase expression. In most of the world’s population, lactase transcription is down-regulated after weaning, resulting in diminished lactase expression in the small intestine. Diminished lactase expression causes the common symptoms of adult-type hypolactasia, or lactose intolerance.

Some population segments exhibit lactase persistence resulting from a mutation that is postulated to have occurred 5000-10,000 years ago, coinciding with the rise of cattle domestication. This mutation has allowed almost half of the world’s population to metabolize lactose without symptoms. Studies have linked the occurrence of lactase persistence to two different single-nucleotide polymorphisms about 14 and 22 kilobases upstream of the 5’-end of the LPH gene. Both mutations, C→T at position -13910 and T→ A at position -22018, have been independently linked to lactase persistence.

The lactase promoter is 150 base pairs long and is located just upstream of the site of transcription initiation. The sequence is highly conserved in mammals, suggesting that critical cis-transcriptional regulators are located nearby. Cdx-2, HNF-1α, and GATA have been identified as transcription factors. Studies of hypolactasia onset have demonstrated that despite polymorphisms there is little difference in lactase expression in infants, showing that the mutations become increasingly relevant during development. Ιt is hypothesized that developmentally-regulated DNA-binding proteins down-regulate transcription or destabilize mRNA transcripts, causing decreased LPH expression after weaning.