PUBLICATION

The myosin chaperone UNC45B is involved in lens development and autosomal dominant juvenile cataract.

Authors
Hansen, L., Comyn, S., Mang, Y., Lind-Thomsen, A., Myhre, L., Jean, F., Eiberg, H., Tommerup, N., Rosenberg, T., Pilgrim, D.
ID
ZDB-PUB-170525-7
Date
2014
Source
European journal of human genetics : EJHG   22(11): 1290-7 (Journal)
Registered Authors
Myhre, Layne, Pilgrim, David
Keywords
none
MeSH Terms
  • Acetyl-CoA Carboxylase/genetics
  • Acetyl-CoA Carboxylase/metabolism
  • Adolescent
  • Adult
  • Animals
  • Cataract/genetics*
  • Child
  • Chromosomes, Human, Pair 17
  • Embryo, Nonmammalian
  • Gene Expression Regulation, Developmental
  • Genetic Loci
  • Genome-Wide Association Study
  • HSP90 Heat-Shock Proteins/genetics
  • HSP90 Heat-Shock Proteins/metabolism
  • Heterozygote
  • Homozygote
  • Humans
  • Immunohistochemistry
  • Lens, Crystalline/cytology
  • Lens, Crystalline/embryology
  • Lens, Crystalline/metabolism
  • Middle Aged
  • Molecular Chaperones/genetics*
  • Molecular Chaperones/metabolism
  • Muscle, Skeletal/metabolism
  • Mutation, Missense
  • Myosins/genetics*
  • Myosins/metabolism
  • Phenotype
  • Young Adult
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
24549050 Full text @ Eur. J. Hum. Genet.
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.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping