HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1−/−mice

• Verfasst von: Webb, Bryn D. [VerfasserIn]
• Verfasst von: Gaspar, Harald [VerfasserIn]
• Verfasst von: Camminady, Anne [VerfasserIn]
• Titel: HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1−/−mice
• Verf.angabe: Bryn D. Webb, Sherin Shaaban, Harald Gaspar, Luis F. Cunha, Christian R. Schubert, Ke Hao, Caroline D. Robson, Wai-Man Chan, Caroline Andrews, Sarah MacKinnon, Darren T. Oystreck, David G. Hunter, Anthony J. Iacovelli, Xiaoqian Ye, Anne Camminady, Elizabeth C. Engle, Ethylin Wang Jabs
• E-Jahr: 2012
• Jahr: July 5, 2012
• Umfang: 9 S.
• Fussnoten: Gesehen am 11.03.2019
• Titel Quelle: Enthalten in: The American journal of human genetics
• Ort Quelle: New York, NY [u.a.] : Cell Press, 1949
• Jahr Quelle: 2012
• Band/Heft Quelle: 91(2012), 1, Seite 171-179
• ISSN Quelle: 1537-6605
• DOI: doi:10.1016/j.ajhg.2012.05.018
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 158850378X

Abstract

Members of the highly conserved homeobox (HOX) gene family encode transcription factors that confer cellular and tissue identities along the antero-posterior axis of mice and humans. We have identified a founder homozygous missense mutation in HOXB1 in two families from a conservative German American population. The resulting phenotype includes bilateral facial palsy, hearing loss, and strabismus and correlates extensively with the previously reported Hoxb1−/− mouse phenotype. The missense variant is predicted to result in the substitution of a cysteine for an arginine at amino acid residue 207 (Arg207Cys), which corresponds to the highly conserved Arg5 of the homeodomain. Arg5 interacts with thymine in the minor groove of DNA through hydrogen bonding and electrostatic attraction. Molecular modeling and an in vitro DNA-protein binding assay predict that the mutation would disrupt these interactions, destabilize the HOXB1:PBX1:DNA complex, and alter HOXB1 transcriptional activity.