Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores.

• 影响指数: 11.043
• 发表时间: 12 2020 3
• 来源期刊: Am J Hum Genet
• DOI: 10.1016/j.ajhg.2020.11.002
• PMID: 33217308
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 生物
• 作者列表: Donkervoort S,Kutzner CE,Hu Y,Lornage X,Rendu J,Stojkovic T,Baets J,Neuhaus SB,Tanboon J,Maroofian R,Bolduc V,Mroczek M,Conijn S,Kuntz NL,Töpf A,Monges S,Lubieniecki F,McCarty RM,Chao KR,Governali S,Böhm J,Boonyapisit K,Malfatti E,Sangruchi T,Horkayne-Szakaly I,Hedberg-Oldfors C,Efthymiou S,Noguchi S,Djeddi S,Iida A,di Rosa G,Fiorillo C,Salpietro V,Darin N,Fauré J,Houlden H,Oldfors A,Nishino I,de Ridder W,Straub V,Pokrzywa W,Laporte J,Foley AR,Romero NB,Ottenheijm C,Hoppe T,Bönnemann CG

关键词: C. elegans; UNC-45; UNC45B; chaperone; core myopathy; muscle; myofibrillar; myosin; sarcomere

Mesh: Adolescent; Adult; Alleles; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins / genetics physiology; Female; Genetic Variation; Humans; Loss of Function Mutation; Male; Molecular Chaperones / genetics physiology; Muscle, Skeletal / pathology; Muscular Diseases / genetics; Mutation, Missense; Myofibrils; Myosins; Sarcomeres / metabolism; Sequence Analysis, RNA; Transgenes; Whole Exome Sequencing; Young Adult

Abstract

The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.