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Understanding the genetic bases of hair disorders holds the promise of better therapies for hypertrichosis and alopecia. Two groups of investigators recently identified a key gene in a novel pathway in the physiology of hair regulation.
Hypotrichosis simplex (HS) is a group of hereditary disorders characterized by alopecia that affect men and women equally. The hair loss is diffuse and progressive and usually begins in early childhood. Pasternack and colleagues identified a consanguineous Saudi Arabian family with HS and performed classic linkage analysis in 11 members of this kindred. They found links to a region on chromosome 13q and identified a homozygous C>T change in P2RY5 that results in a premature stop codon. Two additional, independent, deleterious mutations were found in two other unrelated HS families. The P2Y5 gene product encodes a G protein–coupled receptor. To identify the natural ligand for the G protein-coupled receptor P2Y5, the group screened a number of compounds and found that the agonist oleoyl-L-α-lysophosphatidic acid (LPA) triggers cAMP signaling. The HS-derived P2Y5 mutants appear to abrogate signaling by LPA. In 2006, another group found that mutations in lipase H, the enzyme that generates LPA, also cause hair deficiency.
Woolly hair (WH) is a different phenotype characterized by tightly curled hair; it can occur as part of a syndrome or without systemic manifestations. Studying one family with autosomal recessive, (nonsyndromic) woolly hair (ARWH), Shimomura and colleagues linked the syndrome to a locus within the chromosome 13q region and identified a mutation also in P2RY5. Additional mutations were found in other patients with ARWH. The HS-related P2RY5 mutations are apparently distinct from those implicated in WH.
Pasternack SM et al. G protein–coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat Genet 2008 Mar; 40:329.
Shimomura Y et al. Disruption of P2RY5, an orphan G protein–coupled receptor, underlies autosomal recessive woolly hair. Nat Genet 2008 Mar; 40:335.
Sprecher E. Disentangling the roots of inherited hair disorders. Nat Genet 2008 Mar; 40:265.
Comment
These studies have important implications. The discovery of severe hair defects related to disruption of LPA signaling is both biologically novel and therapeutically enabling. G protein–coupled receptors have been analyzed for decades; the link to a specific ligand makes the system immediately tractable for pharmacologic screening. That two very different phenotypes converge on the same gene is interesting; examination of more families will facilitate larger-scale phenotype–genotype correlation. In the era of large-scale genetics and expensive genomics, it is nice that important discoveries can still be made with the aid of a keen eye and the help of a few families. As dermatologists, we all come across kindreds with interesting phenotypes — it just takes one crucial family to crack a long-standing biological mystery.