2. Academic Validation
  3. Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome

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

  • Am J Hum Genet. 2016 Dec 1;99(6):1292-1304. doi: 10.1016/j.ajhg.2016.10.004.
F Buket Ü Basmanav 1,  Laura Cau 2,  Aylar Tafazzoli 3,  Marie-Claire Méchin 2,  Sabrina Wolf 3,  Maria Teresa Romano 3,  Frederic Valentin 4,  Henning Wiegmann 4,  Anne Huchenq 2,  Rima Kandil 3,  Natalie Garcia Bartels 5,  Arzu Kilic 6,  Susannah George 7,  Damian J Ralser 3,  Stefan Bergner 3,  David J P Ferguson 8,  Ana-Maria Oprisoreanu 9,  Maria Wehner 3,  Holger Thiele 10,  Janine Altmüller 11,  Peter Nürnberg 12,  Daniel Swan 13,  Darren Houniet 13,  Aline Büchner 14,  Lisa Weibel 15,  Nicola Wagner 16,  Ramon Grimalt 17,  Anette Bygum 18,  Guy Serre 2,  Ulrike Blume-Peytavi 5,  Eli Sprecher 19,  Susanne Schoch 9,  Vinzenz Oji 4,  Henning Hamm 20,  Paul Farrant 7,  Michel Simon 2,  Regina C Betz 21
Affiliations

Affiliations

  • 1 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, 37073 Göttingen, Germany; Campus Laboratory for Advanced Imaging, Microscopy and Spectroscopy, University of Göttingen, 37073 Göttingen, Germany.
  • 2 CNRS UMR5165 and INSERM U1056 and University of Toulouse, 31059 Toulouse, France.
  • 3 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
  • 4 Department of Dermatology, University of Münster, 48149 Münster, Germany.
  • 5 Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany.
  • 6 Dermatology Department, Balikesir University School of Medicine, 10100 Balikesir, Turkey.
  • 7 Dermatology Department, Brighton and Sussex University Hospitals NHS Trust, Brighton General Hospital, Elm Grove, Brighton BN2 3EW, UK.
  • 8 Nuffield Department of Clinical Laboratory Science, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
  • 9 Department of Neuropathology and Department of Epileptology, University of Bonn, 53127 Bonn, Germany.
  • 10 Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
  • 11 Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
  • 12 Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
  • 13 Computational Biology Group, Oxford Gene Technology, Oxford OX5 1PF, UK.
  • 14 Pediatric Dermatology Department, University Children's Hospital Zurich, University Hospital of Zurich, 8032 Zurich, Switzerland.
  • 15 Pediatric Dermatology Department, University Children's Hospital Zurich, University Hospital of Zurich, 8032 Zurich, Switzerland; Dermatology Department, University Hospital Zurich, 8032 Zurich, Switzerland.
  • 16 Clinical Center Darmstadt, 64297 Darmstadt, Germany.
  • 17 Universitat Internacional de Catalunya, Sant Cugat del Vallès, 08195 Barcelona, Spain.
  • 18 Department of Dermatology and Allergy Centre, Odense University Hospital, 5000 Odense, Denmark.
  • 19 Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.
  • 20 Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany.
  • 21 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany. Electronic address: regina.betz@uni-bonn.de.
PMID: 27866708 DOI: 10.1016/j.ajhg.2016.10.004
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.

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