A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.
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.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Jinglan
J
Zhang
Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Véronik
V
Lachance
Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Adam
A
Schaffner
Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Xianting
http://orcid.org/0000-0002-3153-0931
X
Li
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Anastasia
A
Fedick
Departments of Anatomy/Cell Biology and Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
Lauren E
LE
Kaye
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Jun
J
Liao
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Jill
http://orcid.org/0000-0001-5664-7987
J
Rosenfeld
Clinical Genetics Services, New York University Hospitals Center, New York, New York, United States of America.
Naomi
N
Yachelevich
Department of Neurology, New York University School of Medicine, New York, New York, United States of America.
Mary-Lynn
ML
Chu
Neurology Division, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
Wendy G
http://orcid.org/0000-0001-8082-1383
WG
Mitchell
Division of Medical Genetics, Children's Hospital Los Angeles, Los Angeles, California, United States of America.|Courtagen Life Sciences, Woburn, Massachusetts, United States of America.
Richard G
RG
Boles
Clinical Genetics Services, NYU Langone Hospital for Joint Diseases, New York, New York, United States of America.
Ellen
E
Moran
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Mari
M
Tokita
Baylor Miraca Genetics Laboratories, Houston, Texas, United States of America.
Elizabeth
E
Gorman
Baylor Miraca Genetics Laboratories, Houston, Texas, United States of America.
Kaytee
http://orcid.org/0000-0002-6218-6942
K
Bagley
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Wei
W
Zhang
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Fan
F
Xia
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Magalie
M
Leduc
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Yaping
Y
Yang
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Christine
C
Eng
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Lee-Jun
LJ
Wong
Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, United States of America.
Raphael
R
Schiffmann
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
George A
GA
Diaz
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Ruth
R
Kornreich
Departments of Anatomy/Cell Biology and Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
Ryan
R
Thummel
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Melissa
M
Wasserstein
Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Zhenyu
Z
Yue
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Lisa
L
Edelmann
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D016923:Cell Death / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D018703:Founder Effect; D005808:Genes, Recessive; D006801:Humans; D007223:Infant; D056784:Leukoencephalopathies / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
C424438:VPS11 protein, human; D033921:Vesicular Transport Proteins