Deletion of 2.7 kb near HOXD3 in an Arabian horse with occipitoatlantoaxial malformation.
Deletion of 2.7 kb near HOXD3 in an Arabian horse with occipitoatlantoaxial malformation.
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DOI：
10.1111/age.12531
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发表时间：
2017-06
期刊：
影响因子：
2.4
通讯作者：
Finno CJ
中科院分区：
文献类型：
--
作者：
Bordbari MH;Penedo MCT;Aleman M;Valberg SJ;Mickelson J;Finno CJ
在马中，术语枕寰枢椎畸形（OAAM）用于描述第一颈椎（寰椎）类似于颅底（枕骨）且第二颈椎（枢椎）类似于寰椎的发育缺陷。受影响的个人表现出异常的姿势和不同程度的共济失调。同源异型盒基因簇（HOX）参与中轴骨和无骨骨骼的发育。Hoxd 3-null小鼠表现出与患有OAAM的阿拉伯马驹惊人相似的表型。全基因组测序进行了一个OAAM受影响的马（OAAM 1）和七个未受影响的阿拉伯马。目视检查HOXD 3区域内的原始读段，鉴定出位于HOXD 4末端下游4.4 kb和HOXD 3起始上游8.2 kb的2.7-kb缺失。基因分型分析显示，OAAM 1的父母都是杂合子的缺失。额外的基因分型确定了162个杂合子阿拉伯人中的两个，其他品种的371匹马中不存在缺失。比较基因组学研究表明，该区域在物种间高度保守，并且Hoxd 4和Hoxd 3之间的整个基因组区域在小鼠中转录。另外两个阿拉伯马驹诊断为OAAM（OAAM 2和3）进行基因分型，并没有2.7 kb的缺失。对这些病例的表型进行更仔细的检查发现了显著的变化。OAAM 3也有面部畸形和动脉导管未闭，颅颈交界处的实际畸形不同。在患有OAAM的阿拉伯马驹中，HOXD基因座可能存在遗传异质性。
In the horse, the term occipitoatlantoaxial malformation (OAAM) is used to describe a developmental defect in which the first cervical vertebra (atlas) resembles the base of the skull (occiput) and the second cervical vertebra (axis) resembles the atlas. Affected individuals demonstrate an abnormal posture and varying degrees of ataxia. The homeobox (HOX) gene cluster is involved in the development of both the axial and appendicular skeleton. Hoxd3-null mice demonstrate a strikingly similar phenotype to Arabian foals with OAAM. Whole-genome sequencing was performed in an OAAM-affected horse (OAAM1) and seven unaffected Arabian horses. Visual inspection of the raw reads within the region of HOXD3 identified a 2.7-kb deletion located 4.4 kb downstream of the end of HOXD4 and 8.2 kb upstream of the start of HOXD3. A genotyping assay revealed that both parents of OAAM1 were heterozygous for the deletion. Additional genotyping identified two of 162 heterozygote Arabians, and the deletion was not present in 371 horses of other breeds. Comparative genomics studies have revealed that this region is highly conserved across species and that the entire genomic region between Hoxd4 and Hoxd3 is transcribed in mice. Two additional Arabian foals diagnosed with OAAM (OAAM 2 and 3) were genotyped and did not have the 2.7-kb deletion. Closer examination of the phenotype in these cases revealed notable variation. OAAM3 also had facial malformations and a patent ductus arteriosus, and the actual malformation at the craniocervical junction differed. Genetic heterogeneity may exist across the HOXD locus in Arabian foals with OAAM.