title: A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family.
abstract: Microtia, a congenital deformity manifesting as an abnormally shaped or absent external ear, occurs in one out of 8,000-10,000 births. We ascertained a consanguineous Iranian family segregating with autosomal-recessive bilateral microtia, mixed symmetrical severe to profound hearing impairment, and partial cleft palate. Genome-wide linkage analysis localized the responsible gene to chromosome 7p14.3-p15.3 with a maximum multi-point LOD score of 4.17. In this region, homeobox genes from the HOXA cluster were the most interesting candidates. Subsequent DNA sequence analysis of the HOXA1 and HOXA2 homeobox genes from the candidate region identified an interesting HOXA2 homeodomain variant: a change in a highly conserved amino acid (p.Q186K). The variant was not found in 231 Iranian and 109 Belgian control samples. The critical contribution of HoxA2 for auditory-system development has already been shown in mouse models. We built a homology model to predict the effect of this mutation on the structure and DNA-binding activity of the homeodomain by using the program Modeler 8v2. In the model of the mutant homeodomain, the position of the mutant lysine side chain is consistently farther away from a nearby phosphate group; this altered position results in the loss of a hydrogen bond and affects the DNA-binding activity.
authors.affiliation: Department of Medical Genetics, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Alasti
authors.forename: Abdorrahim
authors.initials: A
authors.lastname: Sadeghi
authors.forename: Mohammad Hossein
authors.initials: MH
authors.lastname: Sanati
authors.forename: Mohammad
authors.initials: M
authors.lastname: Farhadi
authors.forename: Elliot
authors.initials: E
authors.lastname: Stollar
authors.forename: Thomas
authors.initials: T
authors.lastname: Somers
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics; D017124:Conserved Sequence; D004423:Ear / Q000002:abnormalities*; D005260:Female; D006312:Hearing Loss, Bilateral / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007492:Iran; D008126:Lod Score; D008279:Magnetic Resonance Imaging; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017434:Protein Structure, Tertiary / Q000235:genetics; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000235:genetics; D000099261:Homeobox A1 Protein
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C520321:HOXA2 protein, human