BioWorld International Correspondent

LONDON - The identification of a gene that is responsible for a rare type of inherited hair loss may lead to new treatments for many different conditions that lead to thinning hair or baldness.

Researchers based in Germany and Saudi Arabia have shown that the gene that caused the inherited hair loss encodes a receptor that is present on the surface of hair follicle cells. The team also was able to pinpoint the ligand that stimulates the receptor.

Regina Betz, project leader at the Institute of Human Genetics at the University of Bonn, told BioWorld International: "It is very interesting that the receptor is a member of the group of proteins known as G protein-coupled receptors, as about 50 to 60 percent of drug targets are G protein-coupled receptors. This makes us hope that we might in the future be able to develop drugs that will help to stimulate hair growth, not just for rare causes of hair loss, but also to help people who suffer from more common conditions that lead to hair loss."

Betz, together with Markus Nöthen, professor of genetic medicine at the Life & Brain Centre at the University of Bonn in Germany, and colleagues, reported the findings in a paper in the Feb. 24, 2008, issue of Nature Genetics titled: "G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth."

Ivar von Kügelgen, professor of molecular pharmacology at the University of Bonn, and another co-author of the paper, said: "We can now search selectively for related substances that may be used in therapies for hair loss."

Betz said work currently is under way to find compounds that will stimulate the receptor even more strongly than the naturally occurring ligand. The team also is working on a knock-out mouse that will lack a working copy of the gene encoding the receptor.

Nöthen, Betz and their team studied a Saudi Arabian family in which several members had a diagnosis of hypotrichosis simplex. That inherited disorder is a form of alopecia. Four of the 10 siblings in this family, which was the result of a consanguineous marriage, had begun to lose their hair between the ages of 3 years and 6 years. Two of those four are almost completely bald.

Following a genomewide linkage analysis, and mapping for homozygosity, the researchers were able to identify a gene locus for hypotrichosis simplex on chromosome 13. That area of the genome contains 61 known genes, and the scientists had sequenced 37 of those in the family members before they found a nonsense mutation in a gene called P2RY5. The gene encodes an orphan G protein-coupled receptor called P2Y5.

Further investigations showed that the four siblings affected by hypotrichosis simplex were homozygous for a mutation in P2RY5, and that their parents were heterozygous for the same mutation.

Study of two other families from Saudi Arabia with members affected by hypotrichosis simplex showed that they, too, had a mutation in the same gene. That mutation was slightly different, and shared by those two families. Analysis suggested that the families had a common ancestor with the same condition.

When the researchers examined more than 600 control chromosomes, including more than 200 from people of Arabian origin, they were unable to find either of the two mutations in the P2RY5 gene.

Studies showed that P2RY5 is expressed widely in human and murine tissues, including in skin and hair follicle cells.

The structure of P2Y5 suggested that it will have seven hydrophobic transmembrane regions, which is a feature of G protein-coupled receptors. The team also went on to search for the ligand that binds to P2Y5 and finally identified that as lysophosphatidic acid (LPA). Experiments showed that when LPA binds to P2Y5, it triggers a signal inside the cell, which appears to be needed for the hair follicle to function normally.

Betz said: "Last year, other researchers identified a protein called lipase H as having a role in hair growth. This fits with our discovery, as lipase H and LPA both act in the same pathway. But we are excited that, with the discovery of P2Y5, we have found out how the signal from the LPA/lipase H pathway gets inside the cell."

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