Genetic variations in ion channels influence human hair color

Genetic variations in ion channels influence human hair color


Levels of the human hair color pigment eumelanin, produced by cells found in the skin’s basal epidermis and hair follicles, depend on the cells’ internal pH. Previous studies have found that genetic variations in a human cation-transporting channel called two-pore channel (TPC) 2 can alter the pH of pigment-producing cells, causing hair color to shift from brown to blond.

Researchers used electrophysiological methods and molecular dynamics simulations to uncover how the genetic variations affect channel function. Compared with the wild-type channel, the M484L variant, in which a methionine residue is replaced by leucine, exhibited not only increased basal activity and response to the channel’s lipid ligand PI(3,5)P2, but also larger current amplitudes stemming from a dilated pore.

Analysis of DNA samples from more than 100 donors with blond, brown, or black hair revealed that 7.2% of samples from blond-haired donors were homozygous for the M484L variation, whereas only 2.9% of samples from donors with brown, dark brown, or black hair were homozygous for the same variation.

Patch-clamp experiments on skin cells from donors revealed heightened PI(3,5)P2-driven TPC2 activity in M484L cells, suggesting that the variation ramps up channel activity, ratchets down eumelanin synthesis, and renders hair blond. Because TPCs are implicated in blood vessel formation, cholesterol transport and metabolism, and cancer cell migration, genetic variations in TPCs might have broad impacts on human health, according to the authors.

http://www.pnas.org/content/early/2017/09/13/1705739114

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