Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome
F Buket Ü Basmanav
(1, 2)
,
Laura Cau
(3)
,
Aylar Tafazzoli
(1)
,
Marie-Claire Mechin
(3)
,
Sabrina Wolf
(1)
,
Maria Teresa Romano
(1)
,
Frédéric Valentin
(4)
,
Henning Wiegmann
(4)
,
Anne Huchenq
(3)
,
Rima Kandil
(1)
,
Natalie Garcia Bartels
(5)
,
Arzu Kilic
(6)
,
Susannah George
(7)
,
Damian J Ralser
(1)
,
Stefan Bergner
(1)
,
David J P Ferguson
(8, 9)
,
Ana-Maria Oprisoreanu
(10)
,
Maria Wehner
(1)
,
Holger Thiele
(11)
,
Janine Altmüller
(11)
,
Peter Nurnberg
(11)
,
Daniel Swan
(12)
,
Darren Houniet
(12)
,
Aline Büchner
(13)
,
Lisa Weibel
(13)
,
Nicola Wagner
(14)
,
Ramon Grimalt
(15)
,
Anette Bygum
(16)
,
Guy Serre
(3)
,
Ulrike Blume-Peytavi
(5)
,
Eli Sprecher
(17)
,
Susanne Schoch
(10)
,
Vinzenz Oji
(4)
,
Henning Hamm
(18)
,
Paul Farrant
(7)
,
Michel Simon
(3)
,
Regina C Betz
(1)
1
Institut für Genetik - Universität Bonn / Institute of Genetics - University of Bonn
2 UMG - University Medical Center Göttingen
3 UDEAR - Unité différenciation épidermique et auto-immunité rhumatoïde
4 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
5 Charité - UniversitätsMedizin = Berlin University Medicine
6 Balikesir University School of Medicine
7 BSUH - Brighton and Sussex University Hospitals - NHS Trust
8 University of Oxford
9 John Radcliffe Hospital [Oxford University Hospital]
10 Universität Bonn = University of Bonn
11 Universität zu Köln = University of Cologne
12 Oxford Gene Technology
13 University Children’s Hospital Zurich
14 Clinical Center Darmstadt
15 UIC - Universitat Internacional de Catalunya [Barcelona]
16 Odense University Hospital, Odense
17 Tel Aviv Sourasky Medical Center [Tel Aviv]
18 University Hospital of Würzburg
2 UMG - University Medical Center Göttingen
3 UDEAR - Unité différenciation épidermique et auto-immunité rhumatoïde
4 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
5 Charité - UniversitätsMedizin = Berlin University Medicine
6 Balikesir University School of Medicine
7 BSUH - Brighton and Sussex University Hospitals - NHS Trust
8 University of Oxford
9 John Radcliffe Hospital [Oxford University Hospital]
10 Universität Bonn = University of Bonn
11 Universität zu Köln = University of Cologne
12 Oxford Gene Technology
13 University Children’s Hospital Zurich
14 Clinical Center Darmstadt
15 UIC - Universitat Internacional de Catalunya [Barcelona]
16 Odense University Hospital, Odense
17 Tel Aviv Sourasky Medical Center [Tel Aviv]
18 University Hospital of Würzburg
Laura Cau
- Fonction : Auteur
- PersonId : 1165698
- ORCID : 0000-0002-2480-536X
Marie-Claire Mechin
- Fonction : Auteur
- PersonId : 1168383
- ORCID : 0000-0001-8915-8223
- IdRef : 244163960
Holger Thiele
- Fonction : Auteur
- PersonId : 772045
- ORCID : 0000-0002-0169-998X
Guy Serre
- Fonction : Auteur
- PersonId : 933000
Michel Simon
- Fonction : Auteur
- PersonId : 774633
- ORCID : 0000-0003-3655-6329
- IdRef : 097642843
Résumé
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.