A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family.
Am J Hum Genet
; 82(4): 982-91, 2008 Apr.
Article
em En
| MEDLINE
| ID: mdl-18394579
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cromossomos Humanos Par 7
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Proteínas de Homeodomínio
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Orelha
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Perda Auditiva Bilateral
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Animals
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Female
/
Humans
País/Região como assunto:
Asia
Idioma:
En
Revista:
Am J Hum Genet
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Bélgica