A novel dominant D109A CRYAB mutation in a family with myofibrillar myopathy affects αB-crystallin structure

Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibrils dissolution and abnormal accumulation of degradation products. So far causative mutations have been identified in nine genes encoding Z-disk proteins, including αB-crystallin (CRYAB), a small heat shoc...

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Bibliographic Details
Published in:BBA clinical 2017-06, Vol.7, p.1-7
Main Authors: Fichna, Jakub P., Potulska-Chromik, Anna, Miszta, Przemysław, Redowicz, Maria Jolanta, Kaminska, Anna M., Zekanowski, Cezary, Filipek, Sławomir
Format: Article
Language:English
Subjects:
Bioinformatics
CRYAB
HSPB5
Molecular dynamics
Mutation
Myofibrillar myopathy
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Summary:Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibrils dissolution and abnormal accumulation of degradation products. So far causative mutations have been identified in nine genes encoding Z-disk proteins, including αB-crystallin (CRYAB), a small heat shock protein (also called HSPB5). Here, we report a case study of a 63-year-old Polish female with a progressive lower limb weakness and muscle biopsy suggesting a myofibrillar myopathy, and extra-muscular multisystemic involvement, including cataract and cardiomiopathy. Five members of the proband's family presented similar symptoms. Whole exome sequencing followed by bioinformatic analysis revealed a novel D109A mutation in CRYAB associated with the disease. Molecular modeling in accordance with muscle biopsy microscopic analyses predicted that D109A mutation influence both structure and function of CRYAB due to decreased stability of oligomers leading to aggregate formation. In consequence disrupted sarcomere cytoskeleton organization might lead to muscle pathology. We also suggest that mutated RQDE sequence of CRYAB could impair CRYAB chaperone-like activity and promote aggregation of lens crystallins. •A novel D109A mutation was identified.•Mutation is associated with myofibrillar myopathy, cardiomyopathy and cataract.•D109 mutations decrease stability of the CRYAB hexamer.•The mutated RQDE sequence could impair chaperone-like activity.•Observed aggregation both in muscle and lens leads to multisystemic phenotype.
ISSN:2214-6474
2214-6474
DOI:10.1016/j.bbacli.2016.11.004