PUBLICATION

A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects

Authors
Zhang, J., Lachance, V., Schaffner, A., Li, X., Fedick, A., Kaye, L.E., Liao, J., Rosenfeld, J., Yachelevich, N., Chu, M.L., Mitchell, W.G., Boles, R.G., Moran, E., Tokita, M., Gorman, E., Bagley, K., Zhang, W., Xia, F., Leduc, M., Yang, Y., Eng, C., Wong, L.J., Schiffmann, R., Diaz, G.A., Kornreich, R., Thummel, R., Wasserstein, M., Yue, Z., Edelmann, L.
ID
ZDB-PUB-160428-3
Date
2016
Source
PLoS Genetics   12: e1005848 (Journal)
Registered Authors
Thummel, Ryan
Keywords
Central nervous system, Autophagic cell death, Zebrafish, Hindbrain, Immunoprecipitation, Ubiquitination, Polymerase chain reaction, Neuronal death
MeSH Terms
  • Sequence Homology, Amino Acid
  • Genes, Recessive*
  • Child
  • Autophagy/genetics*
  • Founder Effect*
  • Adult
  • Young Adult
  • Humans
  • Molecular Sequence Data
  • Female
  • Leukoencephalopathies/genetics*
  • Child, Preschool
  • Male
  • Infant
  • Mutation*
  • Animals
  • Amino Acid Sequence
  • Cell Death/genetics
  • Vesicular Transport Proteins/chemistry
  • Vesicular Transport Proteins/genetics*
(all 20)
PubMed
27120463 Full text @ PLoS Genet.
Abstract
Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.
Genes / Markers
Figures
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Expression
No data available
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
wsu1
    Complex
    1 - 1 of 1
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    Human Disease / Model
    Human Disease Fish Conditions Evidence
    leukodystrophyTAS
    1 - 1 of 1
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    Sequence Targeting Reagents
    No data available
    Fish
    1 - 2 of 2
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    Antibodies
    Orthology
    No data available
    Engineered Foreign Genes
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    Mapping
    No data available