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Mandibulofacial dysostosis with alopecia model mice

RIKEN BRC June 2026
Mouse of the Month

Mandibulofacial dysostosis with alopecia model mice

ICR-Ednra<em1(E303K)Hku> (RBRC12041)
ICR-Ednra<em2(Y129F)Hku> (RBRC12042)

Normal mutation

The ETAR_Y129F mutant strain exhibits external abnormalities of the auricles and eyelids. Furthermore, osteochondral staining of newborns reveals the presence of rod-shaped bones with mandibular-like articular cartilage at the maxillary (mx, jg) sites, and the disappearance of the processes (zp, rp) on the quadrate bone (sq). The same phenotype is observed in all cases of the ETAR_E303K mutant strain.

Mandibulofacial dysostosis with alopecia (MFDA) is a rare congenital disorder caused by genetic mutations. Based on previous research and case reports in humans, depositors (Dr. Yukiko Kurihara and her colleagues) focused on the endothelin-1 (Edn1/ET1)/endothelin A receptor (Ednra/ETAR) signaling pathway, which plays a key role in vasoconstriction and morphogenesis. Using the CRISPR/Cas9 genome editing system, depositors generated two strains of mice with amino acid mutations in the ETAR. Both the ETAR E303K mutant strain (RBRC12401), in which glutamic acid was mutated to lysine, and the ETAR Y129F mutant strain (RBRC12402), in which tyrosine was mutated to phenylalanine, exhibited auricular malformations, maxillary bone malformations, and hypoplasia of the ossicles, suggesting hearing loss. These are phenotypes that can also be observed in mandibulofacial dysostosis, a condition characterized by alopecia accompanied by auricular and facial morphological abnormalities and hearing loss. Using these MFDA model mice, depositors elucidate the mechanism by which ETAR mutations cause MFDA at the atomic level by conducting pharmacological experiments and molecular dynamics simulations on a supercomputer [1].
In addition to the RBRC12041 and RBRC12042 MFDA model mouse strains, RIKEN BRC has provided a endothelin-3 (Edn3/ET3) knockout strain (RBRC12043) and a mouse strain (RBRC12044) generated by crossing the RBRC12041 and RBRC12043 strains. The RBRC12044 strain shows that the phenotype caused by the ETAR E303K mutation is rescued by the ET3 knockout. These strains are useful not only developing treatments for MFDA, but also for elucidating disease mechanisms, as mutations in G protein-coupled receptors (GPCRs), to which the ETAR belongs, are known to cause various human diseases.

 

Keywords : Mandibulofacial dysostosis with alopecia (MFDA), a rare congenital disorder, amino acid mutation, Human disease model, G protein-coupled receptor (GPCR)
Depositor : Yukiko Kurihara, M.D., Ph.D. (The University of Tokyo at the time of the strain deposition)
Strain name : ICR-Ednra<em1(E303K)Hku>
RBRC No. : RBRC12041
Strain name : ICR-Ednra<em2(Y129F)Hku>
RBRC No. : RBRC12042
Strain name : ICR-Edn3<em1Hku>
RBRC No. : RBRC12043
Strain name : ICR-Ednra<em1(E303K)Hku>Edn3<em1Hku>
RBRC No. : RBRC12044
Reference : [1] Kurihara Y, Ekimoto T, Gordon CT, Uchijima Y, Sugiyama R, Kitazawa T, Iwase A, Kotani R, Asai R, Pingault V, Ikeguchi M, Amiel J, Kurihara H.
Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding
J Clin Invest. 2023 Feb 15;133(4):e151536.

 

June 2026
Saori Mizuno, Ph.D.
Contact: Experimental Animal Division, RIKEN BioResource Research Center (animal.brc@riken.jp)
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