If baldness is really a genetic trait, then I am well and truly screwed. I come from a long line of cue balls; every male in my family over the age of 30 is bald or balding. Especially worrying is the fact that both my Dad and my maternal Grandfather started thinning in their mid twenties, a fact my Dad takes particular glee in pointing out to me at every available opportunity.
Thus, I greeted a couple of recent articles in Nature Genetics with an air of optimistic hope. Of particular interest to me is the paper by Pasternack et al (citation below), which details a complete a start-to-finish study on the genetics of a rare hair loss disorder, beginning with a genome wide linkage analysis and ending in functional characterisation of the candidate gene: P2Y5. A simultaneous article in the same journal also looked at the involvement of this gene in hair growth, but from a different functional perspective, as covered over at Gene Expression.
Due to the commonality of baldness and the complex pathophysiology of hair growth disorders, finding a genetic cause with therapeutic potential is extremely difficult. This is why studying rare heritable hair loss disorders, such as the specific alopecia condition analysed in this study, offers a unique opportunity to pinpoint some of the key components involved in maintaining normal hair growth.
A powerful approach to advance our understanding of the pathophysiology of human hair loss is to identify genes underlying mendelian isolated alopecias. Investigation of this type of hair loss offers the unique opportunity to identify factors that are not only necessary for, but also specific to, hair growth.
Using an affected Saudi Arabian family, the group mapped the disease locus to a 28Mb region on chromosome 13. Candidate gene sequencing revealed a truncating mutation in the sequence for P2Y5: a gene that codes for a G protein-coupled transmembrane receptor. Normally located on the cell membrane, the group showed accumulation of the truncated protein in the endoplasmic reticulum, suggesting loss of function.
Aside from the solid genetic analysis carried out, the real strength of this paper lies in the further functional analysis of the protein, which did not have a clearly understood function. Through a reporter gene assay and A radiolabelled binding experiment, the group identified lysophosphatidic acid (LPA) as the ligand for the receptor. In addition, they demonstrated in vitro that the truncated version of this protein is unable to elicit the cellular response normally observed after binding of LPA to P2Y5, likely due to the loss of a number of intra-cellular loops that are known to be involved in G protein activation.
LPA is known to bind a number of receptors alongside P2Y5, with a downsteam effect of enhanced cell proliferation and migration. Broadly, these receptors can be classified into two subgroups: LPA1, LPA2 and LPA3 in one group, and LPA4 and LPA5 in the second group. The authors propose the placement of P2Y5 in with this latter subgroup due to its amino acid sequence homology and the similar downstream signalling pathways.
Interestingly, of the latter group of receptors, LPA4 and LPA5 are not expressed in the hair follicle. Thus, a loss of the one member of the group that is, P2Y5, leads to a complete loss of LPA signal transduction through the specific pathway mediated by the group. Further characterisation of this pathway is now required in order to understand how its impairment results in the alopecia phenotype observed in affected individuals however.
Ultimately, the most important question to arise from this study to me is: could it eventually culminate in an effective treatment (or even a cure!) for baldness? While it is conceivable that this paper offers the possibility of identifying potential inducers of the LPA-P2Y5 mediated pathway in a hope of enhancing hair growth in balding individuals, more realistically it offers potential for further elucidation of the complex pathways involved in hair follicle development and function.
Thus, I don’t think I’ll be seeing any wonder-drugs in the crucial next few good-hair years I have left in me that will cease the inevitable chrome-domia before it advances into chronic cue ball-ness.
Pasternack, S.M., von Kugelgen, I., Aboud, K.A., Lee, Y., Ruschendorf, F., Voss, K., Hillmer, A.M., Molderings, G.J., Franz, T., Ramirez, A., Nurnberg, P., Nothen, M.M., Betz, R.C. (2008). G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nature Genetics, 40(3), 329-334. DOI: 10.1038/ng.84
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