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

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.

The biology and genetics of curly hair

“…The interaction of trichohyalin with keratin is preceded by the enzymatic conversion of arginine to citrulline within the trichohyalin by the enzyme peptidyl arginine deiminase (PAD) that reduces its overall charge so facilitating stable interaction with the IRS keratins . So it was very interesting to note that mutations in the trichohyalin gene were described for uncombable hair syndrome, which includes a curly hair phenotype . In addition to TCHH, the genes for PAD (PADI3) and transglutaminase 3 (TGM3), both involved in the transformation of the IRS from “soft” to “hard,” were also mutated in this rare genetic condition.…”

Arachidonate 12-Lipoxygenase Inhibitors Promote S100A3 Citrullination in Cultured SW480 Cells and Isolated Hair Follicles

“…38) Recently, an uncombable hair syndrome causative mutation was reported to exist in PADI3 encoding the hair-dominant PADI isozyme. 6) Our results clearly showed that ALOX12 inhibition efficiently promotes S100A3 citrullination in concert with HBEGF. Further study is needed to elucidate the pharmacological action of ALOX inhibitors on superficial epithelium maturation of skin and hair follicles.…”

Spontaneous Quick Resolution of Uncombable Hair Syndrome-Like Disease

“…There is currently no effective treatment for the condition. Parents are usually advised to avoid excessive hair manipulation and to provide biotin supplementation, until the hair condition improves gradually during puberty [1, 2]. Herein, we report the abrupt and spontaneous resolution of an uncombable hair-like phenotype in a young boy.…”

“…The hair has a frizzy appearance and protrudes from the scalp in several directions, and is resistant to brushing and combing [1, 2]. Most of the cases are sporadic, but familial cases in autosomal recessive or dominant-inheritance patterns have been reported.…”

“…Most of the cases are sporadic, but familial cases in autosomal recessive or dominant-inheritance patterns have been reported. Recently, mutations in 3 genes involved in the production of the structural hair protein trichohyalin have been reported as the cause for some familial cases of UHS [1]. …”