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

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

doi:10.1016/j.ajhg.2012.05.018

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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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.

Original language	English (US)
Pages (from-to)	171-179
Number of pages	9
Journal	American Journal of Human Genetics
Volume	91
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2012.05.018
State	Published - Jul 13 2012

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Webb, B. D., Shaaban, S., Gaspar, H., Cunha, L. F., Schubert, C. R., Hao, K., Robson, C. D., Chan, W. M., Andrews, C., MacKinnon, S., Oystreck, D. T., Hunter, D. G., Iacovelli, A. J., Ye, X., Camminady, A., Engle, E. C., & Jabs, E. W. (2012). HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1 ^-/- mice. American Journal of Human Genetics, 91(1), 171-179. https://doi.org/10.1016/j.ajhg.2012.05.018

Webb, BD, Shaaban, S, Gaspar, H, Cunha, LF, Schubert, CR, Hao, K, Robson, CD, Chan, WM, Andrews, C, MacKinnon, S, Oystreck, DT, Hunter, DG, Iacovelli, AJ, Ye, X, Camminady, A, Engle, EC & Jabs, EW 2012, 'HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1 ^-/- mice', American Journal of Human Genetics, vol. 91, no. 1, pp. 171-179. https://doi.org/10.1016/j.ajhg.2012.05.018

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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.",

author = "Webb, {Bryn D.} and Sherin Shaaban and Harald Gaspar and Cunha, {Luis F.} and Schubert, {Christian R.} and Ke Hao and Robson, {Caroline D.} and Chan, {Wai Man} and Caroline Andrews and Sarah MacKinnon and Oystreck, {Darren T.} and Hunter, {David G.} and Iacovelli, {Anthony J.} and Xiaoqian Ye and Anne Camminady and Engle, {Elizabeth C.} and Jabs, {Ethylin Wang}",

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AU - Schubert, Christian R.

AU - Hao, Ke

AU - Robson, Caroline D.

AU - Chan, Wai Man

AU - Andrews, Caroline

AU - MacKinnon, Sarah

AU - Oystreck, Darren T.

AU - Hunter, David G.

AU - Iacovelli, Anthony J.

AU - Ye, Xiaoqian

AU - Camminady, Anne

AU - Engle, Elizabeth C.

AU - Jabs, Ethylin Wang

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AB - 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.

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

Abstract

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