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. 2008 Apr;82(4):982-91.
doi: 10.1016/j.ajhg.2008.02.015.

A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family

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A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family

Fatemeh Alasti et al. Am J Hum Genet. 2008 Apr.

Erratum in

  • Am J Hum Genet. 2008 Sep;83(3):424

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.

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Figures

Figure 1
Figure 1
Photographs of the Microtic ears of Three Affected Family Members
Figure 2
Figure 2
High-Resolution CT Imaging of Three Patients' Temporal Bones These images (coronal views) present bilateral stenotic ear canals, an incomplete atretic plate, malformed ossicles, and a normal inner ear except in patient IV:3 on the left side.
Figure 3
Figure 3
Pure-Tone Audiometry of Both Ears for All Four Affected Family Members Audiometry was performed at frequencies of 250–8000 Hz for air conduction and 250–4000 Hz for bone conduction.
Figure 4
Figure 4
The Pedigree of the Iranian Consanguineous Family IR-SA-27 Segregating with Autosomal-Recessive Microtia A double marriage line denotes consanguinity. Black symbols represent individuals with microtia, hearing impairment, and partial cleft palate. Clear symbols represent unaffected individuals. The boxed haplotype bars denote the disease–associated haplotype. The genetic-map distance in centi-Morgans (cM) is given in front of the marker names. Haplotypes for the analyzed STRPs are shown below each individual symbol.
Figure 5
Figure 5
ConSeq Conservation Analysis of the Amino Acid Q44 in Homeodomain of the Human HOXA2 Protein This analysis is based on the alignment of 100 full-length members of different HOX gene clusters in different species. Colors indicate the degree of conservation of each residue. In the figure, the alignment of only 18 proteins is shown.
Figure 6
Figure 6
Representative Homology Models of the HOXA2 Homeodomain Bound to DNA Overall schematic diagram of the protein-DNA complex (A) and close-up views of the wild-type (B) and Q44K (C) homeodomains. Hydrogen bonds are indicated by dashed lines.

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