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

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.

VPS41 recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

“…Currently, patients with mutations in HOPS core components VPS11, VPS16 and VPS33A have been reported in literature, which all show a neurodegenerative phenotype (11,(67)(68)(69)(70)(71)(72)(73)(74). Moreover, during our studies, a third patient with compound heterozygote mutations in VPS41 was identified (Personal communication by I. Stolte-Dijkstra, University Medical Center Groningen), bearing the VPS41 R662* mutation as well as a missense mutation (VPS41 H466R ), and displaying a similar neurological phenotype.…”

“…(75)(76)(77). These observations are of particular importance with regards to the design of a possible treatment of HOPS related disorders (69,70,73,78,79).…”

Autophagy in childhood neurological disorders

“…VPS11 is a core subunit of endosomal tethering complexes, which are recruited onto autophagosomes and interact with SNAREs to mediate membrane fusion. As a component of HOPS complex, loss of VPS11 function caused accumulation of p62 and lipidated LC3, indicating that it is required for autophagosome clearance …”

“…As a component of HOPS complex, loss of VPS11 function caused accumulation of p62 and lipidated LC3, indicating that it is required for autophagosome clearance. 21…”

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

“…These events cause cellular stress and ultimately lead to apoptosis, which is especially damaging in neuronal tissues since these post-mitotic cells have little Aflatounian et al, 2016;Arhan et al, 2009;Bull et al, 2006;Cullinane et al, 2009;Cullinane et al, 2010;Elmeery et al, 2013;Giraud et al, 2017;Gissen et al, 2004;Gissen et al, 2006;Hershkovitz et al, 2008;Huang et al, 2017;Ilhan et al, 2016;Jang et al, 2009;Kim et al, 2011;Li et al, 2014;Moon et al, 2017;Saadah et al, 2013;Sanseverino et al, 2006;Seo et al, 2015;Taha et al, 2007;Tornieri et al, 2013;Wang et al, 2014;Weyand et al, 2016;Zhou and Zhang, 2014 regenerative capacity. Mutations in CHEVI or HOPS components commonly cause neurological defects in the C. elegans, D. melanogaster, zebrafish and mice animal models (Fernandes et al, 2014;Harrington et al, 2012;Kim et al, 2004;Peng et al, 2012b;Suzuki et al, 2003;Zhang et al, 2016). Patients carrying mutations in the core components Vps11, Vps16 or Vps33A (Cai et al, 2016;Edvardson et al, 2015;Hörtnagel et al, 2016;Kondo et al, 2017;Zhang et al, 2016) or ARC-causing mutations in the CHEVI subunits also show neurological symptoms (Eastham et al, 2001).…”