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Title: The aetiology and genetics of clubfoot in the peroneal muscular atrophy mouse model
Author: Neves, Carlos Eduardo Sousa
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2013
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The present study is focused on understanding the aetiology of the human clubfoot deformity. Although this pathology has been studied since Classical Antiquity, the mechanisms that lead to this abnormality in new-born patients remain elusive. Clubfoot is a deformity of one or both feet present at birth, in which the foot is abnormally positioned in a hand-like position, that is, the foot is turned and rotated inwards while pointing down; and is resistant to any further movements. Very little is known about the aetiology and genetics of clubfoot in the human population. Only recently, mutations in the PITX1 gene have been associated with a small number of patients. Because the genetic basis is not understood and the phenotypic observations are complex and variable in human patients, many mechanisms have been proposed to explain clubfoot. In this study, these pressing questions were addressed using the peroneal muscular atrophy (pma) mouse, a spontaneous mutant that has been shown to be a surprisingly good model for clubfoot, recapitulating the key features of the human phenotype. In order to confirm that the pma mouse is in fact an idiopathic model of clubfoot, it was important to understand if the pma clubfoot-like phenotype occurs in isolation or within a syndromic pathology. In addition to clubfoot, it was found that these animals show a retinal degeneration phenotype. However, this phenotype was associated with the Pde6brd1 mutation, suggesting that clubfoot occurs independently of the retinal phenotype and thus the pma is a good model for human idiopathic clubfoot. Clubfoot in the pma mouse has been associated with the observed failure of the foot rotation during embryonic development. This defect is thought to result from the extensive regional muscular atrophy that occurs at earlier stages. The peroneal nerve is also absent in the adult pma mouse, a defect that has remained unexplored. As such, this neuronal defect was studied to understand the reason for the peroneal nerve absence in the adult animals. The results indicate that the nerve fails to branch from the developing sciatic nerve during embryogenesis and is unable to innervate its target muscles. This abnormal branching process is associated with a neural growth delay. In respect to the genetics of the pma, it was not possible to identify the exact mutation that is responsible for the inheritance of the clubfoot phenotype. However, strong evidence was found in favour of a regulatory mutation resulting in over-expression of the gene Limk1, which encodes for a kinase involved in neuronal guidance and growth. Further work was performed on chicken embryos to understand the foot rotation process. By removing defined regions of muscle tissue from the developing limb zeugopod, it was possible to conclude that lack of function of the anterior and lateral hindlimb tissue is associated with abnormal foot rotation, resulting in a similar phenotype to clubfoot. By examining the affected muscles, it was possible to identify the tibialis cranialis and the peroneus longus muscles as relevant candidates involved in clubfoot aetiology. In summary, the evidence presented here suggests that the pma clubfoot results from a regulatory mutation that induces Limk1 over-expression and nerve growth delay. This in turn prevents the proper development of the peroneal nerve, resulting in the degeneration of its target muscle tibialis anterior and peroneus longus muscles. This degeneration will interfere with foot rotation and result in clubfoot. Thus, the results described by this work are of utmost importance for the understanding of the clubfoot pathology, as it supports a neuro-muscular aetiology dependent on a physical dynamic equilibrium of muscular forces. This is of scientific interest as it expands the current understanding of the foot rotation and the integrative interactions during the limb organogenesis; poorly described developmental processes, and of clinical relevance as it establishes important ideas and concepts for study in human patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Clubfoot ; Charcot-Marie-Tooth disease