Congenital myasthenic syndrome of Brahman cattle

The postsynaptic congenital myasthenic syndrome that is the subject of this thesis is caused by a deficiency of nAChR at the neuromuscular junction, resulting from homozygosity for a null mutation in the ε-subunit gene (CHRNE 470del20). To date, this represents the only naturally occurring CMS in animals to have been described at the DNA level. This thesis covers all steps from the initial discovery and case description, to the diagnosis, development of a diagnostic test, and screening of the population, to predictive modelling and assessment of its impact on the Brahman breed. In Chapter 2, the first presentation of calves with CMS is described. The clinical presentation was quite unlike that of any disease previously described in cattle, but reminiscent of myasthenia gravis in dogs and other animals. This prompted the author to pursue appropriate diagnostic and therapeutic approaches, resulting in a presumptive diagnosis of postsynaptic “congenital myasthenia gravis”, or CMS. The publication of the first case report led to collaboration with the German group of Steinlein and Sieb in order to identify the underlying mutation. Although the bovine CHRNE complementary DNA (cDNA) sequence had previously been described (Takai et al., 1985), its genomic sequence had not. The description of the genomic structure of bovCHRNE and the discovery of the mutation responsible for the disease, a 20 base pair deletion in exon 5 of the gene, is the subject of Chapter 3. In Chapter 4, the development and validation of a PCR screening test for the mutation is described. The chapter discusses the results of initial screening for the mutation, both amongst relatives of the then known carrier bulls and amongst unrelated animals, to obtain an initial estimate of the frequency of the mutation. Clinical findings from another affected calf are also described. Wider screening of the South African registered Brahman cattle population was then undertaken, in collaboration with the BCBSSA. The results of this screening to date are presented in Chapter 5. A more precise estimate of the mutation frequency in the population, and its change over time, is thus obtained. Chapter 5 also addresses the question of whether there is any selective advantage associated with an animal being heterozygous for the mutation. In addition, pedigree analysis is carried out in order to identify ancestral carriers of the mutation and thus determine its origin in the South African population. In order to control a recessive disease-causing mutation such as CMS in a livestock population, it is necessary to know how the frequency is expected to change over time. In Chapter 6, a spreadsheet model is described that predicts the change in mutation frequency over time in a population, under certain assumptions. The model allows for fitness to vary between genotypes, between sexes and over time. It can thus be used to model mutation frequency where there is heterozygote advantage or disadvantage and/or when various control measures are implemented. Finally, Chapter 7 contains a general discussion of what is currently known about CMS in Brahman cattle. The most important issues arising from each chapter are highlighted, and the implications of CMS for the Brahman breed in South Africa are discussed