title: The myosin chaperone UNC45B is involved in lens development and autosomal dominant juvenile cataract.
abstract: Genome-wide linkage analysis, followed by targeted deep sequencing, in a Danish multigeneration family with juvenile cataract revealed a region of chromosome 17 co-segregating with the disease trait. Affected individuals were heterozygous for two potentially protein-disrupting alleles in this region, in ACACA and UNC45B. As alterations of the UNC45B protein have been shown to affect eye development in model organisms, effort was focused on the heterozygous UNC45B missense mutation. UNC45B encodes a myosin-specific chaperone that, together with the general heat shock protein HSP90, is involved in myosin assembly. The mutation changes p.Arg805 to Trp in the UCS domain, an amino acid that is highly conserved from yeast to human. UNC45B is strongly expressed in the heart and skeletal muscle tissue, but here we show expression in human embryo eye and zebrafish lens. The zebrafish mutant steif, carrying an unc45b nonsense mutation, has smaller eyes than wild-type embryos and shows accumulation of nuclei in the lens. Injection of RNA encoding the human wild-type UNC45B protein into the steif homozygous embryo reduced the nuclei accumulation and injection of human mutant UNC45B cDNA in wild-type embryos resulted in development of a phenotype similar to the steif mutant. The p.Arg805Trp alteration in the mammalian UNC45B gene suggests that developmental cataract may be caused by a defect in non-muscle myosin assembly during maturation of the lens fiber cells.
authors.affiliation: 1] Wilhelm Johannsen Centre for Functional Genome Research, Panum Institute, University of Copenhagen, Copenhagen, Denmark [2] Institute of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.affiliation: Department of Biological Sciences, CW-405 Biological Sciences Building, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Comyn
authors.affiliation: 1] Wilhelm Johannsen Centre for Functional Genome Research, Panum Institute, University of Copenhagen, Copenhagen, Denmark [2] Institute of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mang
authors.affiliation: 1] Wilhelm Johannsen Centre for Functional Genome Research, Panum Institute, University of Copenhagen, Copenhagen, Denmark [2] Institute of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Lind-Thomsen
authors.affiliation: Department of Biological Sciences, CW-405 Biological Sciences Building, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Layne
authors.initials: L
authors.lastname: Myhre
authors.affiliation: Department of Biological Sciences, CW-405 Biological Sciences Building, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Francesca
authors.initials: F
authors.lastname: Jean
authors.affiliation: Institute of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Eiberg
authors.affiliation: 1] Wilhelm Johannsen Centre for Functional Genome Research, Panum Institute, University of Copenhagen, Copenhagen, Denmark [2] Institute of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: 1] Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark [2] National Eye Clinic for the Visually Impaired, Department of Ophthalmology, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
authors.affiliation: Department of Biological Sciences, CW-405 Biological Sciences Building, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Pilgrim
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D002386:Cataract / Q000235:genetics*; D002648:Child; D002886:Chromosomes, Human, Pair 17; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007908:Lens, Crystalline / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D020125:Mutation, Missense; D009218:Myosins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D055815:Young Adult; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D009124:Muscle Proteins; C000598852:UNC45B protein, human; C472790:Unc45b protein, zebrafish; D029961:Zebrafish Proteins; D009218:Myosins; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase