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

Jakub P Fichna; Anna Potulska-Chromik; Przemysław Miszta; Maria Jolanta Redowicz; Anna M Kaminska; Cezary Zekanowski; Sławomir Filipek

doi:10.1016/j.bbacli.2016.11.004

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

BBA Clin. 2016 Nov 11:7:1-7. doi: 10.1016/j.bbacli.2016.11.004. eCollection 2017 Jun.

Authors

Jakub P Fichna¹, Anna Potulska-Chromik², Przemysław Miszta³, Maria Jolanta Redowicz⁴, Anna M Kaminska², Cezary Zekanowski¹, Sławomir Filipek³

Affiliations

¹ Laboratory of Neurogenetics, Department of Neurodegenerative Disorders, Mossakowski Medical Research Center, Polish Academy of Sciences, 02-106 Warszawa, 5 Pawinskiego St., Poland.
² Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097 Warsaw, Poland.
³ Faculty of Chemistry and Biological and Chemical Research Centre, University of Warsaw, 1 Pasteur St., 02-093 Warsaw, Poland.
⁴ Laboratory of Molecular Basis of Cell Motility, Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland.

Abstract

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.

Keywords: Bioinformatics; CRYAB; HSPB5; Molecular dynamics; Mutation; Myofibrillar myopathy.