Hypomyelination and developmental delay associated with<i>VPS11</i>mutation in Ashkenazi-Jewish patients

Edvardson, Simon; Gerhard, Frank; Jalas, Chaim; Lachmann, Jens; Golan, Dafna; Saada, Ann; Shaag, Avraham; Ungermann, Christian; Elpeleg, Orly

doi:10.1136/jmedgenet-2015-103239

Cited by 43 publications

(47 citation statements)

References 27 publications

(16 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 62%

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VPS41recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

Jobling

Burns

et al. 2019

Preprint

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The vacuolar protein sorting protein 41 (VPS41) is a neuroprotective protein in models of Parkinson's disease (PD). As part of the HOPS (Homotypic fusion and Protein Sorting) complex, VPS41 regulates fusion of lysosomes with late endosomes and autophagosomes. Independent of HOPS, VPS41 regulates transport of newly synthesized lysosomal membrane proteins and secretory proteins. Here we report two brothers with compound heterozygous mutations in VPS41 (VPS41 R662* and VPS41 S285P ), born to healthy and non-consanguineous parents. Both patients displayed transient retinal dystrophy, ataxia and dystonia, with brain MRI findings of cerebellar atrophy and a thin saber-shape corpus callosum. Patient-derived fibroblasts contained enzymatically active lysosomes that were poorly reached by endocytic cargo and failed to attract the mTORC1 complex. Consequently, transcription factor TFE3, a driver of autophagy and lysosomal genes, showed continuous nuclear localization which resulted in elevated LC3-II levels and an impaired response to nutrient starvation. CRISPR/CAS VPS41 HeLa knockout cells showed a similar phenotype that could be rescued by wildtype VPS41 but not by VPS41 S285P or VPS41 R662* . mTORC1 inhibition was also seen after knockout of HOPS subunits VPS11 or VPS18. Regulated neuropeptide secretion in PC12 VPS41 knockout cells was rescued by VPS41 S285P expression, indicating that this HOPS-independent function was preserved. Co-expression of the VPS41 S285P and VPS41 R662* variants in a C. elegans model of PD abolished the protective effect of VPS41 against α-synuclein-induced neurodegeneration. We conclude that both disease-associated VPS41 variants specifically abrogate HOPS function, which leads to a delay in endocytic cargo delivery to lysosomes, mTORC1 inhibition and irresponsiveness to autophagic clues. Our studies signify a link between HOPS function and mTORC1 signaling and imply that HOPS function is required for the neuroprotective effect of VPS41 in PD.

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Section: Discussionmentioning

confidence: 62%

“…(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).…”

Section: Discussionmentioning

confidence: 89%

VPS41recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

Jobling

Burns

et al. 2019

Preprint

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“…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). Intriguingly, mutations in Vps3 or Vps8 seemingly do not impact neuronal function (Lorincz et al, 2016).…”

Section: Neurological Defectsmentioning

confidence: 99%

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

Beek

Jonker

Welle

et al. 2019

Journal of Cell Science

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Multisubunit tethering complexes (MTCs) are multitasking hubs that form a link between membrane fusion, organelle motility and signaling. CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. They regulate the major membrane flows required for endocytosis, lysosome biogenesis, autophagy and phagocytosis. In addition, individual subunits control complex-independent transport of specific cargoes and exert functions beyond tethering, such as attachment to microtubules and SNARE activation. Mutations in CHEVI subunits lead to arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, while defects in CORVET and, particularly, HOPS are associated with neurodegeneration, pigmentation disorders, liver malfunction and various forms of cancer. Diseases and phenotypes, however, vary per affected subunit and a concise overview of MTC protein function and associated human pathologies is currently lacking. Here, we provide an integrated overview on the cellular functions and pathological defects associated with CORVET, CHEVI or HOPS proteins, both with regard to their complexes and as individual subunits. The combination of these data provides novel insights into how mutations in endo-lysosomal proteins lead to human pathologies.

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“…Affected HLD12 patients manifest severely delayed or even lack of psychomotor development, acquired microcephaly, lack of speech, and often lack of spontaneous movement due to hypotonia and spasticity. Brain MRI shows hypomyelination and thin corpus callosum (46).…”

Section: Hypomyelinating Leukodystrophy 12 (Vps11 Related Disorder -Hmentioning

confidence: 99%

Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology

Charzewska¹,

Wierzba

Iżycka‐Świeszewska

et al. 2016

Clinical Genetics

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Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.

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Hypomyelination and developmental delay associated withVPS11mutation in Ashkenazi-Jewish patients

Cited by 43 publications

References 27 publications

VPS41recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

VPS41recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

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

Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology

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