title: 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.
authors.affiliation: 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.
authors.forename: F Buket
authors.initials: FB
authors.lastname: Ü Basmanav
authors.affiliation: CNRS UMR5165 and INSERM U1056 and University of Toulouse, 31059 Toulouse, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Cau
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Aylar
authors.initials: A
authors.lastname: Tafazzoli
authors.affiliation: CNRS UMR5165 and INSERM U1056 and University of Toulouse, 31059 Toulouse, France.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Méchin
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wolf
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Romano
authors.affiliation: Department of Dermatology, University of Münster, 48149 Münster, Germany.
authors.forename: Frederic
authors.initials: F
authors.lastname: Valentin
authors.affiliation: Department of Dermatology, University of Münster, 48149 Münster, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Wiegmann
authors.affiliation: CNRS UMR5165 and INSERM U1056 and University of Toulouse, 31059 Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Huchenq
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Rima
authors.initials: R
authors.lastname: Kandil
authors.affiliation: Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Garcia Bartels
authors.affiliation: Dermatology Department, Balikesir University School of Medicine, 10100 Balikesir, Turkey.
authors.forename: Arzu
authors.initials: A
authors.lastname: Kilic
authors.affiliation: Dermatology Department, Brighton and Sussex University Hospitals NHS Trust, Brighton General Hospital, Elm Grove, Brighton BN2 3EW, UK.
authors.forename: Susannah
authors.initials: S
authors.lastname: George
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Ralser
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bergner
authors.affiliation: Nuffield Department of Clinical Laboratory Science, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: David J P
authors.initials: DJP
authors.lastname: Ferguson
authors.affiliation: Department of Neuropathology and Department of Epileptology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Oprisoreanu
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Wehner
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Computational Biology Group, Oxford Gene Technology, Oxford OX5 1PF, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Swan
authors.affiliation: Computational Biology Group, Oxford Gene Technology, Oxford OX5 1PF, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Houniet
authors.affiliation: Pediatric Dermatology Department, University Children's Hospital Zurich, University Hospital of Zurich, 8032 Zurich, Switzerland.
authors.forename: Aline
authors.initials: A
authors.lastname: Büchner
authors.affiliation: Pediatric Dermatology Department, University Children's Hospital Zurich, University Hospital of Zurich, 8032 Zurich, Switzerland; Dermatology Department, University Hospital Zurich, 8032 Zurich, Switzerland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Weibel
authors.affiliation: Clinical Center Darmstadt, 64297 Darmstadt, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Wagner
authors.affiliation: Universitat Internacional de Catalunya, Sant Cugat del Vallès, 08195 Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Grimalt
authors.affiliation: Department of Dermatology and Allergy Centre, Odense University Hospital, 5000 Odense, Denmark.
authors.forename: Anette
authors.initials: A
authors.lastname: Bygum
authors.affiliation: CNRS UMR5165 and INSERM U1056 and University of Toulouse, 31059 Toulouse, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Serre
authors.affiliation: Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Blume-Peytavi
authors.affiliation: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.affiliation: Department of Neuropathology and Department of Epileptology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schoch
authors.affiliation: Department of Dermatology, University of Münster, 48149 Münster, Germany.
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Oji
authors.affiliation: Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Hamm
authors.affiliation: Dermatology Department, Brighton and Sussex University Hospitals NHS Trust, Brighton General Hospital, Elm Grove, Brighton BN2 3EW, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Farrant
authors.affiliation: CNRS UMR5165 and INSERM U1056 and University of Toulouse, 31059 Toulouse, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Simon
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany. Electronic address: regina.betz@uni-bonn.de.
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
mesh_terms: D000293:Adolescent; D000818:Animals; D000941:Antigens / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D018389:Codon, Nonsense; D005260:Female; D006197:Hair / Q000002:abnormalities / Q000033:anatomy & histology / Q000254:growth & development* / Q000378:metabolism; D006201:Hair Diseases / Q000235:genetics*; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D011487:Protein Conformation; D000080063:Protein-Arginine Deiminase Type 3; D000076342:Protein-Arginine Deiminases; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014738:Vibrissae / Q000002:abnormalities
chemical_list: D000941:Antigens; D018389:Codon, Nonsense; D007381:Intermediate Filament Proteins; C479420:TCHH protein, human; C498712:TGM3 protein, human; D011503:Transglutaminases; D006867:Hydrolases; C000609098:PAD3 protein, mouse; C000619078:PADI3 protein, human; D000080063:Protein-Arginine Deiminase Type 3; D000076342:Protein-Arginine Deiminases