Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome

作者：Basmanav F Buket U; Cau Laura; Tafazzoli Aylar; Mechin Marie Claire; Wolf Sabrina; Romano Maria Teresa; Valentin Frederic; Wiegmann Henning; Huchenq Anne; Kandil Rima; Bartels Natalie Garcia; Kilic Arzu; George Susannah; Ralser Damian J; Bergner Stefan; Ferguson David J P; Oprisoreanu Ana Maria; Wehner Maria; Thiele Holger; Altmueller Janine; Nuerenberg Peter; Swan Daniel; Houniet Darren; Buechner Aline; Weibel Lisa; Wagner Nicola; Grimalt Ramon; Bygum Anette

来源：American Journal of Human Genetics, 2016, 99(6): 1292-1304.

DOI：10.1016/j.ajhg.2016.10.004

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 wildtype 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.

• 出版日期2016-12-1