Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs.
Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs.
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犬类疾病反映了人类疾病：HES7 中的外显子缺失会导致小型雪纳瑞犬发生常染色体隐性遗传性脊椎肋骨发育不全。
DOI：
10.1371/journal.pone.0117055
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Wade CM
中科院分区：
文献类型：
--
作者：
Willet CE;Makara M;Reppas G;Tsoukalas G;Malik R;Haase B;Wade CM
脊椎肋骨发育不全是一种先天性中轴骨骼疾病，在不同种族背景的人类家庭中均有记载。这种情况的特点是躯干缩短，广泛的半椎骨和肋骨异常，包括对线不良，融合和数量减少。Notch信号通路基因DLL 3、MESP 2、LFNG、HES 7和TBX 6的突变与这种缺陷有关。在这项研究中，脊椎肋骨发育不全在远交家庭的小型雪纳瑞犬。计算机断层扫描显示，这种情况反映了在人类病例中观察到的骨骼缺陷，但与大多数人类病例不同的是，受影响的狗是死胎或出生后不久死亡。通过基因定位和全基因组测序，我们确定了HES 7编码区的单碱基缺失。移码突变导致丢失的功能结构域的振荡转录自抑制HES 7在体节发生过程中必不可少的。限制性片段长度多态性试验应用于直系亲属，并支持高度外显常染色体隐性遗传模式。在对117只随机抽样的成年小型雪纳瑞犬和6只成年标准雪纳瑞犬进行的更广泛的测试中，未观察到突变;提供了P raw = 4.759e-36（全基因组显著性）的显著关联。尽管这种明显的低频率在澳大利亚的人口，等位基因可能是全球分布的基础上，它的存在于两个不相关的父系从地理上遥远的位置。虽然在少数其他犬种中观察到孤立的半椎骨，但这是第一次在非人类哺乳动物中自发发生脊椎肋骨发育不全的临床和遗传诊断，并提供了一个研究这种破坏性人类疾病的极好模型。遗传测试可以被狗饲养者用来选择远离疾病，避免不必要的新生儿损失。
Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of P raw = 4.759e-36 (genome-wide significant). Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.
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