胚胎期和围生期肌球蛋白基因突变评估及先天性特发性马蹄内翻足的病因学研究
Evaluation of embryonic and perinatal myosin gene mutations and the etiology of congenital idiopathic clubfoot.
作者信息
Shyy William, Wang Kai, Sheffield Val C, Morcuende Jose A
机构信息
Department of Orthopaedic Surgery, University of Iowa, Iowa City, IA, USA.
出版信息
J Pediatr Orthop. 2010 Apr-May;30(3):231-4. doi: 10.1097/BPO.0b013e3181d35e3f.
BACKGROUND
Congenital idiopathic clubfoot is the most common musculoskeletal birth defect that develops during the fetal period, but with no known etiology. MYH 2, 3, 7, and 8 are expressed embryonically or perinatally, the period during which congenital idiopathic clubfoot develops; are all components of Type II muscle, which is consistently decreased in clubfoot patients; and are associated with several muscle contracture syndromes that have associated clubfoot deformities. In this study, we hypothesized that a mutation in an embryonic or perinatal myosin gene could be associated with congenital idiopathic clubfoot.
METHODS
We screened the exons, splice sites, and predicted promoters of 24 bilateral congenital idiopathic clubfoot patients and 24 matched controls in MYH 1, 2, 3, and 8 via sequence-based analysis, and screened an additional 76 patients in each discovered SNP.
RESULTS
Although many single-nucleotide polymorphisms were found; none proved to be significantly associated with the phenotype of congenital idiopathic clubfoot. Also, no known mutations that cause distal arthrogryposis syndromes were found in the congenital idiopathic clubfoot patients.
CONCLUSIONS
These findings demonstrate that congenital idiopathic clubfoot has a different pathophysiology than the clubfoot seen in distal arthrogryposis syndromes, and defects in myosin are most likely not directly responsible for the development of congenital clubfoot. Given the complexity of early myogenesis, many regulatory candidate genes remain that could cause defects in the hypaxial musculature that is invariably observed in congenital idiopathic clubfoot.
CLINICAL RELEVANCE
This study further differentiates congenital idiopathic clubfoot as distinct from other complex genetic syndromes that can present with similar deformities, and thus facilitates further research to improve the clinical diagnosis and treatment of congenital idiopathic clubfoot.
背景
先天性特发性马蹄内翻足是胎儿期最常见的肌肉骨骼先天性缺陷，但病因不明。肌球蛋白重链2、3、7和8在胚胎期或围产期表达，而先天性特发性马蹄内翻足正是在这一时期形成；它们均为Ⅱ型肌的组成成分，而马蹄内翻足患者的Ⅱ型肌一直减少；并且它们与几种伴有马蹄内翻足畸形的肌肉挛缩综合征有关。在本研究中，我们推测胚胎期或围产期肌球蛋白基因突变可能与先天性特发性马蹄内翻足有关。
方法
我们通过基于序列的分析，对24例双侧先天性特发性马蹄内翻足患者及24例匹配对照的肌球蛋白重链1、2、3和8的外显子、剪接位点及预测启动子进行筛查，并对每个发现的单核苷酸多态性额外筛查76例患者。
结果
虽然发现了许多单核苷酸多态性，但均未被证明与先天性特发性马蹄内翻足的表型显著相关。此外，在先天性特发性马蹄内翻足患者中未发现已知的导致远端关节弯曲综合征的突变。
结论
这些发现表明，先天性特发性马蹄内翻足的病理生理学与远端关节弯曲综合征中的马蹄内翻足不同，肌球蛋白缺陷很可能不是先天性马蹄内翻足形成的直接原因。鉴于早期肌发生的复杂性，仍有许多调控候选基因可能导致先天性特发性马蹄内翻足中始终存在的轴下肌肉组织缺陷。
临床意义
本研究进一步区分了先天性特发性马蹄内翻足与其他可能出现类似畸形的复杂遗传综合征，从而有助于进一步研究以改善先天性特发性马蹄内翻足的临床诊断和治疗。
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