The pma mouse and the developmental basis of congenital talipes equinovarus (clubfoot)

马蹄内翻足（医学术语：先天性马蹄内翻足或CTEV）影响500个孩子中的1个，花费NHS数百万美元。这种常见的先天性足部姿势障碍阻止了脚底放在地面上行走。治疗是通过几个月的连续石膏铸造和支撑，有时手术。有些病人对治疗的反应不令人满意。治疗后小腿肌肉和足部形状仍然存在，并会给孩子和家庭带来相当大的负担。考虑到马蹄内翻足很常见，而且会毁容，它会显著影响生活质量，是NHS的主要负担，你会认为它的遗传基础会得到很好的研究。事实上，与其他类似的常见疾病如唇腭裂相比，发育生物学家对潜在机制的细节研究很少。如果我们知道遗传缺陷是什么，我们就可以在受影响的家庭中筛选它们并开发新的疗法。如果我们有一种老鼠患上了马蹄内翻足，我们可以筛选它的基因突变，我们可以看到脚是如何出错的，并确定哪些医疗或环境因素可能使马蹄内翻足更好或更糟。我们认为pma小鼠品系相当于人类的马蹄内翻足。它的后足扭曲变形，看起来很像马蹄内翻足。这个项目的目的是研究这些老鼠的脚，观察骨骼和软组织，看看它们是否真的和人类的马蹄内翻足一样。我们将在pma小鼠中鉴定突变基因，并筛选人类患者的DNA，看看该基因的人类版本是否在马蹄内翻足中突变。我们将确定在胚胎发育的哪个阶段脚开始出问题。这将表明是否有可能用新药、基因治疗或早期手术进行干预，以在影响患者的生活质量之前挽救或治愈马蹄内翻足。我们应该能够利用这些知识来改善患者的生活，简化治疗，减轻NHS的负担。

Clubfoot (medical term: congenital talipes equinovarus or CTEV) affects 1 in 500 kids and costs the NHS millions. This common inborn disorder of foot posture prevents the sole of the foot being placed on the ground for walking. Treatment is by months of serial plaster casting and bracing, and sometimes surgery. Some patients do not satisfactorily respond to treatment. Abnormalities of calf muscle and foot shape remain after treatment, and can bring a considerable burden to the child and family. Given that clubfoot is common and disfiguring, that it significantly affects quality of life, and is a major burden on the NHS, you would think that its genetic basis would be well studied. In fact, in contrast to other similarly common conditions like cleft lip and palate, the detail of the underlying mechanism has been little studied by developmental biologists. If we knew what the genetic defects were, we could screen for them in affected families and develop new therapies. If we had a type of mouse that developed clubfoot, we could screen its genes for the mutation and we could see how the foot goes wrong and identify what medical or environmental factors might make clubfoot better or worse. We propose that the mouse strain pma is the equivalent of human clubfoot. Its hindfeet are distorted in a way that looks very like clubfoot. The aim of this project is to study the feet of these mice, to look at the bones and soft tissues to see if they really are the same as human clubfoot. We will identify the mutant gene in pma mice, and screen the DNA of human patients to see if the human verison of the gene is mutated in clubfoot. We will determine what stage the feet start to go wrong during embryogenesis. This will show whether or not it is going to be possible to intervene with new drugs, with gene therapy or with early surgery to rescue or cure he clubfoot before it impacts on the quality of life of the patients. We should be able to use this knowledge to improve the life of patients, streamline treatment to reduce the burden on the NHS.