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

Lead Research Organisation: University of Aberdeen
Department Name: Institute of Medical Sciences


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.

Technical Summary

Idiopathic congenital talipes equinovarus (CTEV) ? clubfoot- affects one or both feet in 1 in 500 children. The aetiology is multifactorial with a genetic contribution, the nature of which remains largely unexplained. Developments in treatment are hampered by lack of understanding of the primary aetiology. We propose the spontaneous mouse mutant pma (peroneal muscular atrophy), as a model for CTEV. The gene defect in pma is unknown. Using magnetic resonance imaging (MR) we have shown that the bones of the pma/pma hindfoot are displaced in the manner seen in CTEV, and there is similar wasting of the calf muscles. Intriguingly, heterozygotes have unilateral clubfoot. Limited data describes neuromuscular and vascular anomalies in CTEV. We seek to validate pma as a model for CTEV by 1) comparative MR studies of pma and human CTEV to demonstrate soft tissue anomalies in muscle, tendon and nerve and 2) demonstration of the genetic defect in pma, and screening the homologous gene in our large collection of samples from CTEV families.

We will also determine the developmental aetiology of pma mutants by molecular analysis of neuromuscular and limb mesenchyme patterning in pma, with emphasis on the specification and pathfinding of motor neurones in the peroneal nerve. We will identify the gene defect by performing fine genetic linkage mapping and by analysis of candidate genes within the region of Chromosome 5 to which pma has been mapped. Candidate pma genes will be screened in our pre-existing human CTEV DNA database. Reporter transgenics will be used to investigate changes in cell signalling pathways in the developing pma/pma hindlimb in vivo. The hindlimb phenotype of an experimentally induced putative chicken model of clubfoot will be compared to pma and human CTEV, and both models will be used to test the role of environmental chemicals, primarily folate, on the severity and expression of the clubfoot phenotype.

Our team of scientists and clinician researchers with track records in CTEV research, mouse and human genetics, developmental biology, and MRI, are uniquely placed to perform this study and translate advances made to the clinic. Explanation of the genetic basis of CTEV, and the availability of a valid model, will enable development of improved treatment strategies, and may be of value in prevention. The MR studies could additionally lead to identification of prognostic factors for treatment, and the work may additionally inform understanding of other limb disorders.


10 25 50