Myofibrillar myopathy caused by novel dominant negative αB-crystallin mutations

We here report the second and third mutations in alphabeta-crystallin causing myofibrillar myopathy. Two patients had adult-onset muscle weakness. Patient 1 had cervical, limb girdle, and respiratory muscle weakness and died of respiratory failure. Patient 2 had proximal and distal leg muscle weakness. Both had myopathic electromyogram with abnormal electrical irritability and muscle biopsy findings of myofibrillar myopathy and mild denervation. Myofibrillar disintegration begins at the Z-disk and results in abnormal local expression of desmin, alphabeta-crystallin, dystrophin, neural cell adhesion molecule (NCAM), and CDC2 kinase. Seven to 8% of nuclei display early apoptotic changes. Both patients carry a truncating mutation in the C-terminal region of alphabeta-crystallin (464delCT in Patient 1 and Q151X in Patient 2) which is crucial for the solubilization and chaperone functions of the molecule. cDNA analysis shows the same mutations and no alternatively spliced transcripts. Immunoblots of muscle demonstrate increased expression of wild-type and reduced expression of the mutant protein. Immunoblots under nondenaturing conditions show that the mutant protein forms lower than normal molecular weight multimeric complexes with wild type. We conclude that (1) despite its reduced expression, the mutant protein exerts a dominant negative effect; (2) mutations in alphabeta-crystallin are an infrequent cause of myofibrillar myopathy; (3) alphabeta-crystallin-related myopathies display phenotypic heterogeneity.