Here we investigate the effects of a myopathy-causing mutation in B-crystallin, Q151X, upon its structure and function. This mutation removes the C-terminal domain of B-crystallin, which is expected to compromise both its oligomerisation and chaperone activity. We compared this to two other B-crystallin mutants (450delA, 464delCT) and also to a series of C-terminal truncations (E164X, E165X, K174X and A171X). We find that the effects of the Q151X mutation were not always as predicted. Specifically, we have found that although the Q151X mutation decreased oligomerisation of B-crystallin and even increased some chaperone activities. It also significantly destabilized B-crystallin causing it to self-aggregate. This conclusion was supported by our analyses of both the other disease causing mutants and the series of C-terminal truncation constructs of B-crystallin. The 450delA and 464delCT mutants could only be refolded and assayed as a complex with wild type B-crystallin, which was not the case for Q151X B-crystallin. From these studies, we conclude that all three disease-causing mutations (450delA, 464delCT and Q151X) in the C-terminal extension destabilise B-crystallin and increase its tendency to self-aggregate. We propose that it is this, rather than a catastrophic loss of chaperone activity, which is a major factor in the development of the reported diseases for the three disease-causing mutations studied here. In support of this hypothesis, we show that Q151X B-crystallin is found mainly in the insoluble fraction of cell extracts from transient transfected cells, due to the formation of cytoplasmic aggregates.