HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1[superscript −/−] Mice
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 America...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2014
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| Online Access: | http://hdl.handle.net/1721.1/91521 |
| _version_ | 1811092877029146624 |
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| author | 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 Oystreck, Darren T. Hunter, David G. Iacovelli, Anthony J. Ye, Xiaoqian Camminady, Anne Engle, Elizabeth C. Jabs, Ethylin Wang Schubert, Christian R. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology 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 Oystreck, Darren T. Hunter, David G. Iacovelli, Anthony J. Ye, Xiaoqian Camminady, Anne Engle, Elizabeth C. Jabs, Ethylin Wang Schubert, Christian R. |
| author_sort | Webb, Bryn D. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:32:10Z |
| format | Article |
| id | mit-1721.1/91521 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:32:10Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/915212022-09-29T14:50:37Z HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1[superscript −/−] Mice 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 Oystreck, Darren T. Hunter, David G. Iacovelli, Anthony J. Ye, Xiaoqian Camminady, Anne Engle, Elizabeth C. Jabs, Ethylin Wang Schubert, Christian R. 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 Schubert, Christian R. 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. National Human Genome Research Institute (U.S.) (Grant U54 HG003067) Swiss National Science Foundation National Institutes of Health (U.S.) (Grant R01 EY15298) National Institutes of Health (U.S.) (Grant R01 HD018655) National Institutes of Health (U.S.) (Grant U54 HG003067) 2014-11-12T13:25:32Z 2014-11-12T13:25:32Z 2012-07 2012-04 Article http://purl.org/eprint/type/JournalArticle 00029297 1537-6605 http://hdl.handle.net/1721.1/91521 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 en_US http://dx.doi.org/10.1016/j.ajhg.2012.05.018 The American Journal of Human Genetics Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier |
| spellingShingle | 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 Oystreck, Darren T. Hunter, David G. Iacovelli, Anthony J. Ye, Xiaoqian Camminady, Anne Engle, Elizabeth C. Jabs, Ethylin Wang Schubert, Christian R. HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1[superscript −/−] Mice |
| title | HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1[superscript −/−] Mice |
| title_full | HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1[superscript −/−] Mice |
| title_fullStr | HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1[superscript −/−] Mice |
| title_full_unstemmed | HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1[superscript −/−] Mice |
| title_short | HOXB1 Founder Mutation in Humans Recapitulates the Phenotype of Hoxb1[superscript −/−] Mice |
| title_sort | hoxb1 founder mutation in humans recapitulates the phenotype of hoxb1 superscript mice |
| url | http://hdl.handle.net/1721.1/91521 |
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