BAG3‐related myofibrillar myopathy in a Chinese family

Abstract

In contrast to the usual slow disease progression in myofibrillar myopathies, patients with Bag3opathy often have a rapidly progressive and more severe phenotype with a worse prognosis. We describe a Chinese patient, born to non-consanguineous parents, who first presented at age 6 with clumsy walking and difficult climbing staircase. With a history of restrictive lung disease previously diagnosed as asthma, she progressed rapidly with proximal myopathy, rigid spine and bilateral tightening of the Achilles tendons requiring surgical elongation. Hypertrophic cardiomyopathy with restrictive physiology was shown by echocardiogram. Moreover, prolonged QT interval was also noted in the patient. Family history was unremarkable yet her father was incidentally found to have prolonged QT interval. Mutation analysis with genomic DNA of the proband showed heterozygous de novo known mutation c.626C>T (p.Pro209Leu) and a germline variation c.772C>T (p.Arg258Trp) in BAG3. Her father was found to be a carrier of c.772C>T. Muscle biopsy findings were suggestive of myofibrillar myopathy on light microscopy and ultrastructural studies. To our knowledge, this is the first Chinese case of Bag3opathy so far reported.

Dilated cardiomyopathy-associatedBAG3mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes

“…Although the Arg258Trp mutation was recently reported in a Chinese patient with MFM, it was also found in the unaffected father of the patient and the patient carried another mutation Pro209Leu [Lee et al, 2011]. In this study, we demonstrated that the MFM-associated Pro209Leu mutation impaired the differentiation of skeletal muscle cell line C2C12, although it caused no functional alterations in the NRCs and in a cardiomyocyte cell line H9c2.…”

“…In addition, Bag3 knockout mice displayed degeneration of muscle fibers with apoptotic nuclei in the striated muscles, resulting in a severe form of skeletal myopathy and cardiomyopathy, which lead to a hypothesis that BAG3 protein might play a role as a Z-disc signaling molecule [Homma et al, 2006]. In accordance with the hypothesis, apart from the association with DCM described above [Norton et al, 2011;Villard et al, 2011], a heterozygous Pro209Leu mutation was found in patients with myofibrillar myopathy (MFM) accompanied by cardiomyopathy (MFM6; MIM# 612954) [Lee et al, 2011;Odgerel et al, 2010;Selcen et al, 2009]. Moreover, it was demonstrated that knockdown of bag3 in a zebrafish model developed heart failure resembling to human DCM [Norton et al, 2011].…”

“…For this purpose, we constructed GFP-tagged BAG3 of WT and DCM-associated mutations, Arg218Trp and Leu462Pro. We also tested an MFM-associated mutation, Pro209Leu [Lee et al, 2011;Odgerel et al, 2010;Selcen et al, 2009], and a nondiseaserelated missense variant, Arg258Trp (Fig. 1A), which was found in one patient and 11 controls in this study.…”

Myofibrillar Myopathies and the Z-Disk Associated Proteins

“…Pathology: atrophic fibres; focal myofibrillar disorganisation and degeneration; sarcoplasmic accumulation of granulofilamentous material. Classified as MFM [227] c.652C>T…”

“…Since then 10 additional Bag3 mutations have been reported of which nine result in DCM [225,226] and one in MFM [227] (Table 7). BAG3 is one of six members of the BAG family of proteins.…”