Alasti Fatemeh, Sadeghi Abdorrahim, Sanati Mohammad Hossein, Farhadi Mohammad, Stollar Elliot, Somers Thomas, Van Camp Guy
Department of Medical Genetics, University of Antwerp, 2610 Antwerp, Belgium.
Am J Hum Genet. 2008 Apr;82(4):982-91. doi: 10.1016/j.ajhg.2008.02.015.
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.
小耳畸形是一种先天性畸形，表现为外耳形状异常或缺失，在8000至10000例出生中出现1例。我们确定了一个伊朗近亲家庭，该家庭中存在常染色体隐性双侧小耳畸形、混合性对称性重度至极重度听力障碍以及部分腭裂。全基因组连锁分析将致病基因定位到7号染色体p14.3 - p15.3区域，最大多点LOD评分为4.17。在该区域，来自HOXA基因簇的同源框基因是最具研究价值的候选基因。随后对候选区域的HOXA1和HOXA2同源框基因进行DNA序列分析，发现了一个有趣的HOXA2同源异型域变体：一个高度保守氨基酸的改变（p.Q186K）。在231例伊朗对照样本和109例比利时对照样本中未发现该变体。HoxA2对听觉系统发育的关键作用已在小鼠模型中得到证实。我们使用Modeler 8v2程序构建了一个同源模型，以预测该突变对同源异型域结构和DNA结合活性的影响。在突变同源异型域模型中，突变赖氨酸侧链的位置始终离附近的磷酸基团更远；这种位置改变导致氢键丢失并影响DNA结合活性。
