Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 4, 982-991, 03 April 2008
doi:10.1016/j.ajhg.2008.02.015
Article
A Mutation in HOXA2 Is Responsible for Autosomal-Recessive Microtia in an Iranian Family
Fatemeh Alasti1, 2, Abdorrahim Sadeghi2, 3, 8, Mohammad Hossein Sanati4, Mohammad Farhadi5, Elliot Stollar6, Thomas Somers7 and Guy Van Camp1, 
, 
1 Department of Medical Genetics, University of Antwerp, 2610 Antwerp, Belgium
2 Department of Molecular Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
3 Department of biology, the faculty of sciences, Tarbiat modarres University, Tehran, Iran
4 Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
5 Iran Cochlear Implant Center, Rassoul-e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
6 Hospital for Sick Children, Department of Molecular Structure and Function, Toronto, Ontario, Canada
7 University Department of Otolaryngology, St. Augustinus Hospital, University of Antwerp, Antwerp, Belgium
Corresponding author8 Present address: Faculty of Medicine, The Arak University of Medical Sciences, Arak, Iran.
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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