Mutation in <i>BAG3</i> causes severe dominant childhood muscular dystrophy

TLDR

Myofibrillar myopathies are genetically heterogeneous muscular dystrophies marked by Z‑disk disintegration, myofibril loss, ectopic protein accumulation, and often cardiomyopathy, neuropathy, and dominant inheritance, with BAG3—a Z‑disk protein possessing anti‑apoptotic properties—being implicated in severe myopathy when deleted in mice. We searched for mutations in BAG3 in 53 unrelated MFM patients. Mutations in alphaB‑crystallin, desmin, myotilin, Zasp, or filamin‑C were identified in 32 of 85 patients in the Mayo MFM cohort.

Abstract

Myofibrillar myopathies (MFMs) are morphologically distinct but genetically heterogeneous muscular dystrophies in which disintegration of Z disks and then of myofibrils is followed by ectopic accumulation of multiple proteins. Cardiomyopathy, neuropathy, and dominant inheritance are frequent associated features. Mutations in alphaB-crystallin, desmin, myotilin, Zasp, or filamin-C can cause MFMs and were detected in 32 of 85 patients of the Mayo MFM cohort. Bag3, another Z-disk-associated protein, has antiapoptotic properties, and its targeted deletion in mice causes fulminant myopathy with early lethality. We therefore searched for mutations in BAG3 in 53 unrelated MFM patients.