Mutations in three genes encoding proteins involved in hair shaft formation cause uncombable hair syndrome

Ü Basmanav, F.B.; Cau, L.; Tafazzoli, A.; Méchin, M.C.; Wolf, S.; Romano, M.T.; Valentin, F.; Wiegmann, H.; Huchenq, A.; Kandil, R.; Garcia Bartels, N.; Kilic, A.; George, S.; Ralser, D.J.; Bergner, S.; Ferguson, D.J.P.; Oprisoreanu, A.M.; Wehner, M.; Thiele, H.; Altmüller, J.; Nürnberg, P.; Swan, D.; Houniet, D.; Büchner, A.; Weibel, L.; Wagner, N.; Grimalt, R.; Bygum, A.; Serre, G.; Blume-Peytavi, U.; Sprecher, E.; Schoch, S.; Oji, V.; Hamm, H.; Farrant, P.; Simon, M.; Betz, R.C.

Mutations in three genes encoding proteins involved in hair shaft formation cause uncombable hair syndrome

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Item Type:	Article
Title:	Mutations in three genes encoding proteins involved in hair shaft formation cause uncombable hair syndrome
Creators Name:	Ü Basmanav, F.B., Cau, L., Tafazzoli, A., Méchin, M.C., Wolf, S., Romano, M.T., Valentin, F., Wiegmann, H., Huchenq, A., Kandil, R., Garcia Bartels, N., Kilic, A., George, S., Ralser, D.J., Bergner, S., Ferguson, D.J.P., Oprisoreanu, A.M., Wehner, M., Thiele, H., Altmüller, J., Nürnberg, P., Swan, D., Houniet, D., Büchner, A., Weibel, L., Wagner, N., Grimalt, R., Bygum, A., Serre, G., Blume-Peytavi, U., Sprecher, E., Schoch, S., Oji, V., Hamm, H., Farrant, P., Simon, M. and Betz, R.C.
Abstract:	Uncombable hair syndrome (UHS), also known as “spun glass hair syndrome,” “pili trianguli et canaliculi,” or “cheveux incoiffables” is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. Elucidation of the molecular outcomes of the disease-causing mutations by cell culture experiments and tridimensional protein models demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins. Scanning electron microscopy observations revealed morphological alterations in hair coat of Padi3 knockout mice. All together, these findings elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology in general.
Keywords:	Antigens, Base Sequence, Cell Line, Hair, Hair Diseases, Hydrolases, Intermediate Filament Proteins, Knockout Mice, Missense Mutation, Molecular Models, Mutation, Nonsense Codon, Protein Conformation, Protein-Arginine Deiminases, Protein-Arginine Deiminase Type 3, Transglutaminases, Vibrissae, Animals, Mice
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Elsevier / Cell Press
Volume:	99
Number:	6
Page Range:	1292-1304
Date:	1 December 2016
Additional Information:	Copyright © 2016 American Society of Human Genetics.
Official Publication:	https://doi.org/10.1016/j.ajhg.2016.10.004
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