title: A novel dominant D109ACRYABmutation in a family with myofibrillar myopathy affects αB-crystallin structure.
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 inCRYABassociated 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.
authors.affiliation: Laboratory of Neurogenetics, Department of Neurodegenerative Disorders, Mossakowski Medical Research Center, Polish Academy of Sciences, 02-106 Warszawa, 5 Pawinskiego St., Poland.
authors.forename: Jakub P
authors.initials: JP
authors.lastname: Fichna
authors.affiliation: Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Potulska-Chromik
authors.affiliation: Faculty of Chemistry and Biological and Chemical Research Centre, University of Warsaw, 1 Pasteur St., 02-093 Warsaw, Poland.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Miszta
authors.affiliation: Laboratory of Molecular Basis of Cell Motility, Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland.
authors.forename: Maria Jolanta
authors.initials: MJ
authors.lastname: Redowicz
authors.affiliation: Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097 Warsaw, Poland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Kaminska
authors.affiliation: Laboratory of Neurogenetics, Department of Neurodegenerative Disorders, Mossakowski Medical Research Center, Polish Academy of Sciences, 02-106 Warszawa, 5 Pawinskiego St., Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Zekanowski
authors.affiliation: Faculty of Chemistry and Biological and Chemical Research Centre, University of Warsaw, 1 Pasteur St., 02-093 Warsaw, Poland.
authors.forename: Sławomir
authors.initials: S
authors.lastname: Filipek
keywords: Bioinformatics; CRYAB; HSPB5; Molecular dynamics; Mutation; Myofibrillar myopathy