title: HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1-/- mice.
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.
authors: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors: Bryn D
authors: BD
authors: Webb
authors: Sherin
authors: S
authors: Shaaban
authors: Harald
authors: H
authors: Gaspar
authors: Luis F
authors: LF
authors: Cunha
authors: Christian R
authors: CR
authors: Schubert
authors: Ke
authors: K
authors: Hao
authors: Caroline D
authors: CD
authors: Robson
authors: Wai-Man
authors: WM
authors: Chan
authors: Caroline
authors: C
authors: Andrews
authors: Sarah
authors: S
authors: MacKinnon
authors: Darren T
authors: DT
authors: Oystreck
authors: David G
authors: DG
authors: Hunter
authors: Anthony J
authors: AJ
authors: Iacovelli
authors: Xiaoqian
authors: X
authors: Ye
authors: Anne
authors: A
authors: Camminady
authors: Elizabeth C
authors: EC
authors: Engle
authors: Ethylin Wang
authors: EW
authors: Jabs
mesh_terms: D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005158:Facial Paralysis / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D020331:Mobius Syndrome / Q000235:genetics; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D013285:Strabismus / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins