Title
A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
New York, N.Y. ,
Subject
Human medicine
Source (journal)
The American journal of human genetics. - New York, N.Y.
Volume/pages
82(2008) :4 , p. 982-991
ISSN
0002-9297
ISI
000255103900016
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Microtia, a congenital deformity manifesting as an abnormally shaped or absent external ear, occurs in one out of 8,00010,000 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
Full text (open access)
https://repository.uantwerpen.be/docman/irua/426221/cf8e0cf3.pdf
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