endothelin-1 and Alopecia

The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.

Topics: Alopecia; Animals; Base Sequence; Endothelin-1; Exome; Humans; In Situ Hybridization; Mandibulofacial Dysostosis; Molecular Sequence Data; Morpholinos; Mutation, Missense; Pedigree; Real-Time Polymerase Chain Reaction; Receptor, Endothelin A; RNA, Messenger; Sequence Analysis, DNA; Syndrome; Tomography, X-Ray Computed; Zebrafish; Zygoma

Regulation of the hair cycle takes place at the pilo-sebaceous unit with the sebaceous gland as a sex hormone-dependent part. Although minoxidil stimulates proliferation of follicular cells and activation of prostaglandin endoperoxide synthase-1, it was suggested that other mechanisms, such as an increase in the local blood flow, might mediate the drug effect on hair growth. If that is the case, it is possible that minoxidil counteracts some vasoconstrictive mediator of male-pattern alopecia. This hypothetical vasoconstrictive mediator X would have to meet some criteria: (I) vasoconstriction both in the general circulation and in the hair-growing skin; (II) local vasoconstrictive activity in the hair growing skin should be related to the circulating testosterone level; (III) only an increase in the local mediator X activity causes male-pattern alopecia, since hypertensive patients are not balder than expected. The sebaceous gland is a possible place of the mediator X secretion since it is a sex-hormone-dependent part of the pilo-sebaceous unit. ET-1 might be a suitable candidate for the mediator X, since male hormones raise ET-1 plasma levels and female hormones lower them. The speculation presented here is that ET-1, beside vasoconstriction in the general circulation, might also regulate the sebum secretion, by triggering contractions of the myoepithelial cells. This hypothetical mechanism would normally remain confined to the sebaceous gland. During puberty, sex hormones stimulate growth of sebaceous glands in both sexes. In women hypertrophied sebaceous glands under estrogen control would not increase its ET-1 content, while in men, testosterone would increase ET-1 secretion that might affect the neighboring arterioles. Induced vasoconstriction might reduce the hair growth and promote hair loss. If ET-1 plays the described role, then an ET-1 antagonist, i.e. bosentane, should also have some hair-growing properties.

Topics: Alopecia; Endothelin-1; Estrogens; Humans; Male; Minoxidil; Models, Theoretical; Sebum; Testosterone; Vasoconstriction; Vasodilator Agents