A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes

Gershlick, David C.; Ishida, Morié; Jones, Julie R.; Bellomo, Allison; Bonifacino, Juan S.; Everman, David B.

doi:10.1093/hmg/ddy423

Cited by 44 publications

(37 citation statements)

References 40 publications

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“…A single 6-year-old patient has recently been reported with compound heterozygous mutations (c.1468C>T/p.Asp745Thrfs*93 and c.2232delC/p.Arg490Cys) in VPS51 (Gershlick et al, 2019).…”

Section: Discussionmentioning

confidence: 97%

“…The observation of Gershlick and colleagues (Gershlick et al, 2019) that not only the proteasomal degradation of VPS51 but also a single aminoacid substitution in its sequence can result in a decreased stability and/or efficiency of the whole GARP and EARP complexes indicates that VPS51 integrity is essential to GARP/EARP function. Of interest, the substitution reported in this paper is 16-aminoacid close to the Phenylalanine deletion observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Loss-of-function mutations in VPS53 have been associated with two forms of degenerative NDDs, autosomal recessive pontocerebellar hypoplasia type 2E (PCH2E, MIM #615851), characterized by a severe early-onset neurodegeneration with profound intellectual disability (ID), progressive microcephaly, spasticity, and early-onset epilepsy (Feinstein et al, 2014), and progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) characterized by a severe developmental delay, limb and facial edema, intractable epilepsy, optic atrophy and dysmorphic features (Hady-Cohen et al, 2018). Recently, a 6-year-old patient with severe global developmental delay, pontocerebellar abnormalities, microcephaly, hypotonia, epilepsy and several systemic and peripheral dysfunctions has been reported (Gershlick et al, 2019). This girl was found to carry compound heterozygous variants in VPS51 affecting both GARP and EARP complexes.…”

Section: Introductionmentioning

confidence: 99%

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VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report

Uwineza

Caberg

Hitayezu

et al. 2019

European Journal of Medical Genetics

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Genome-wide linkage analysis and whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sortingassociated protein, one the four subunits of the GARP and EARP complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.

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“…A single 6-year-old patient has recently been reported with compound heterozygous mutations (c.1468C>T/p.Asp745Thrfs*93 and c.2232delC/p.Arg490Cys) in VPS51 (Gershlick et al, 2019).…”

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report

Uwineza

Caberg

Hitayezu

et al. 2019

European Journal of Medical Genetics

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“…Mutations in the gene encoding the VPS54 subunit, which lead to a drastic reduction in levels of VPS54 and disturb the GARP complex assembly, result in spinal muscular atrophy in the “wobbler” mouse that is considered as a model for ALS [ 103 ]. Recently, mutations in two others GARP complex subunits, VPS53 and VPS51, have been associated with a complex form of HSP and a neurodevelopmental disorder in patients, respectively, demonstrating the importance of this complex in the pathway [ 77 , 104 ].…”

Section: Alteration Of the Endolysosomal Pathway In Hspmentioning

confidence: 99%

Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Marchesi

Leblanc

Stevanin

2021

Cells

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Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP.

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“…Both the GARP and EARP complexes are required for dendrite regrowth in c4da neurons after developmental pruning in pupae. The emergence of this phenotype only at later developmental stages is reminiscent of the secondary microcephaly that emerges postnatally in patients with GARP/EARP complex mutations (Feinstein et al, 2014;Gershlick et al, 2018;Hady-Cohen et al, 2018).…”

Section: Garp and Earp In Neurodevelopmentmentioning

confidence: 99%

Loss of the GARP but not EARP protein complex drives Golgi sterol overload during dendrite remodeling

Jan

2021

Preprint

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Membrane trafficking is essential for sculpting neuronal morphology. The GARP and EARP complexes are conserved tethers that regulate vesicle trafficking in the secretory and endolysosomal pathways, respectively. Both complexes contain the Vps51, Vps52, and Vps53 proteins, and a complex-specific protein: Vps54 in GARP and Vps50 in EARP. In Drosophila, we find that both complexes are required for dendrite morphogenesis during developmental remodeling of multidendritic class IV da (c4da) neurons. Having found that sterol accumulates at the trans-Golgi network (TGN) in Vps54KO/KO neurons, we investigated genes that regulate sterols and related lipids at the TGN. Overexpression of oxysterol binding protein (Osbp) or knockdown of the PI4K four wheel drive (fwd) exacerbates the Vps54KO/KO phenotype, whereas eliminating one allele of Osbp rescues it, suggesting that excess sterol accumulation at the TGN is, in part, responsible for inhibiting dendrite regrowth. These findings distinguish the GARP and EARP complexes in neurodevelopment and implicate vesicle trafficking and lipid transfer pathways in dendrite morphogenesis.

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A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes

Cited by 44 publications

References 40 publications

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report

Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Loss of the GARP but not EARP protein complex drives Golgi sterol overload during dendrite remodeling

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