Viable EdnraY129Fmice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation.
Animal models resembling human mutations are valuable tools to research the features of complex human craniofacial syndromes. This is the first report on a viable dominant mouse model carrying a non-synonymous sequence variation within the endothelin receptor type A gene (Ednra c.386A>T, p.Tyr129Phe) derived by an ENU mutagenesis program. The identical amino acid substitution was reported recently as disease causing in three individuals with the mandibulofacial dysostosis with alopecia (MFDA, OMIM 616367) syndrome. We performed standardized phenotyping of wild-type, heterozygous, and homozygous EdnraY129Fmice within the German Mouse Clinic. Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals. As observed in MFDA-affected individuals, mutant EdnraY129Fmice exhibit hearing impairment in line with strong abnormalities of the ossicles and further, reduction of some lung volumetric parameters. In general, heterozygous and homozygous mice demonstrated inter-individual diversity of expression of the craniofacial phenotypes as observed in MFDA patients but without showing any cleft palates, eyelid defects, or alopecia. Mutant EdnraY129Fmice represent a valuable viable model for complex human syndromes of the first and second pharyngeal arches and for further studies and analysis of impaired endothelin 1 (EDN1)-endothelin receptor type A (EDNRA) signaling. Above all, EdnraY129Fmice model the recently published human MFDA syndrome and may be helpful for further disease understanding and development of therapeutic interventions.
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|Research Unit Comparative Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
Sibylle
S
Sabrautzki
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
Michael A
MA
Sandholzer
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
Bettina
B
Lorenz-Depiereux
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
Robert
R
Brommage
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Gerhard
G
Przemeck
Department of Neurology, Friedrich-Baur-Institut, University Hospital of LMU Munich, Ziemssenstr. 1, 80336, Munich, Germany.|German Center for Vertigo and Balance Disorders, 81377, Munich, Germany.
Ingrid L
IL
Vargas Panesso
Department of Neurology, Friedrich-Baur-Institut, University Hospital of LMU Munich, Ziemssenstr. 1, 80336, Munich, Germany.|German Center for Vertigo and Balance Disorders, 81377, Munich, Germany.
Alexandra
A
Vernaleken
Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
Lillian
L
Garrett
Ludwig-Boltzmann Gesellschaft GmbH, Ludwig-Boltzmann Institut for Clinical-Forensic Imaging (LBI CFI), BioTechMed Graz, Universitätsplatz 4/2, 8010, Graz, Austria.
Katharina
K
Baron
Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
Ali O
AO
Yildirim
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.|Molecular Nutritional Medicine, Else Kröner-Fresenius Center and ZIEL Research Center for Nutrition and Food Science, Technische Universität München, Gregor-Mendel-Str. 2, 85350, Freising-Weihenstephan, Germany.
Jan
J
Rozman
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|Gene Center of the Ludwig-Maximilians-Universität München, Chair for Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 25, 81377, Munich, Germany.
Birgit
B
Rathkolb
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Christine
C
Gau
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Wolfgang
W
Hans
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
Sabine M
SM
Hoelter
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
Susan
S
Marschall
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
Claudia
C
Stoeger
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.|Department of Neurology, Friedrich-Baur-Institut, University Hospital of LMU Munich, Ziemssenstr. 1, 80336, Munich, Germany.|German Center for Vertigo and Balance Disorders, 81377, Munich, Germany.
Lore
L
Becker
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Helmut
H
Fuchs
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Valerie
V
Gailus-Durner
Molecular Nutritional Medicine, Else Kröner-Fresenius Center and ZIEL Research Center for Nutrition and Food Science, Technische Universität München, Gregor-Mendel-Str. 2, 85350, Freising-Weihenstephan, Germany.
Martin
M
Klingenspor
Department of Neurology, Friedrich-Baur-Institut, University Hospital of LMU Munich, Ziemssenstr. 1, 80336, Munich, Germany.|German Center for Vertigo and Balance Disorders, 81377, Munich, Germany.|Munich Cluster for System Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Schillerstr. 44, 80336, Munich, Germany.
Thomas
T
Klopstock
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.
Christoph
C
Lengger
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Leuchtenberger
L
Stefanie
Gene Center of the Ludwig-Maximilians-Universität München, Chair for Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 25, 81377, Munich, Germany.
Eckhard
E
Wolf
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|Institut für Humangenetik, Klinikum rechts der Isar der Technischen Universität München, Trogerstr. 32, 81675, Munich, Germany.
Tim M
TM
Strom
Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|Munich Cluster for System Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Schillerstr. 44, 80336, Munich, Germany.|Chair of Developmental Genetics at Technische Universität München-Weihenstephan, Helmholtz Zentrum München, Ingolstädter Landstr.1, 85764, Neuherberg, Germany.|German Center for Neurodegenerative Diseases (DZNE) Site Munich, Feodor-Lynen-Str. 17, 81377, Munich, Germany.
Wolfgang
W
Wurst
Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr.1, 85764, Neuherberg, Germany. hrabe@helmholtz-muenchen.de.|German Center for Diabetes Research (DZD), Neuherberg, Germany. hrabe@helmholtz-muenchen.de.|Lehrstuhl für Experimentelle Genetik, Technische Universität München, 85350, Freising-Weihenstephan, Germany. hrabe@helmholtz-muenchen.de.
Martin Hrabě
MH
de Angelis
D000505:Alopecia / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D005838:Genotype; D006801:Humans; D008342:Mandibulofacial Dysostosis / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D009154:Mutation; D010641:Phenotype; D044022:Receptor, Endothelin A / Q000235:genetics*; D015398:Signal Transduction
D044022:Receptor, Endothelin A
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