HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1[superscript −/−] Mice
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Webb-2012-HOXB1 Founder Mutati.pdf
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Author(s)
Webb, Bryn D.
Shaaban, Sherin
Gaspar, Harald
Cunha, Luis F.
Schubert, Christian R.
Hao, Ke
Robson, Caroline D.
Chan, Wai-Man
Andrews, Caroline
MacKinnon, Sarah
Date Issued
July 2012
Journal
The American Journal of Human Genetics
Publisher
Elsevier
Citation
Webb, Bryn D., Sherin Shaaban, Harald Gaspar, Luis F. Cunha, Christian R. Schubert, Ke Hao, Caroline D. Robson, et al. “HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1−/− Mice.” The American Journal of Human Genetics 91, no. 1 (July 2012): 171–179. © 2012 The American Society of Human Genetics
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Final published version
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[superscript −/−] 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.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Massachusetts Institute of Technology. Research Laboratory of Electronics
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DOI of Published Version
https://doi.org/10.1016/j.ajhg.2012.05.018
