A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures

Segel, Reeval; Aran, Adi; Gülsüner, Süleyman; Nakamura, Hajime; Rosen, Tzvia; Walsh, Tom; Denda, Hiroto; Zeligson, Sharon; Eto, Katsuki; Beeri, Rachel; Okai, Haruka; King, Mary Claire; Levy‐Lahad, Ephrat; Funato, Kouichi; Renbaum, Paul

doi:10.1007/s10048-020-00615-4

Cited by 9 publications

(22 citation statements)

References 16 publications

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“…Previous studies in yeast have indicated that Arv1p, although non-essential for growth and therefore GPI-anchoring of proteins at 25˚C [39,40], is required for the efficient synthesis of Man 1 GlcN-acylPI (mannosyl-glucosaminyl-acyl-phosphatidylinositol) [41] It has been postulated to be a GPI flippase [41,42] helping deliver GlcN-acylPI, which is made on the cytoplasmic face of the ER, to the active site of mannosyl-transferase I (MT I) on the luminal face of the ER. The complementation of yeast Arv1 mutants by the human Arv1 [43] and recent findings that human Arv1 mutations lead to deficiencies in GPI anchoring [44,45] strongly suggest a related role in mammalian cells. However, whether it is a component of the mammalian and yeast UDP-GlcNAc: PI α1-6 GlcNAc-transferase complexes, or indeed of possible GlcNAc-PI de-N-acetylase of GPI flippase complexes, is unclear.…”

Section: Discussionmentioning

confidence: 88%

Proteomic identification of the UDP-GlcNAc: PI α1–6 GlcNAc-transferase subunits of the glycosylphosphatidylinositol biosynthetic pathway of Trypanosoma brucei

Ji¹,

Tinti²,

Ferguson³

2021

PLoS ONE

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The first step of glycosylphosphatidylinositol (GPI) anchor biosynthesis in all eukaryotes is the addition of N-acetylglucosamine (GlcNAc) to phosphatidylinositol (PI) which is catalysed by a UDP-GlcNAc: PI α1–6 GlcNAc-transferase, also known as GPI GnT. This enzyme has been shown to be a complex of seven subunits in mammalian cells and a similar complex of six homologous subunits has been postulated in yeast. Homologs of these mammalian and yeast subunits were identified in the Trypanosoma brucei predicted protein database. The putative catalytic subunit of the T. brucei complex, TbGPI3, was epitope tagged with three consecutive c-Myc sequences at its C-terminus. Immunoprecipitation of TbGPI3-3Myc followed by native polyacrylamide gel electrophoresis and anti-Myc Western blot showed that it is present in a ~240 kDa complex. Label-free quantitative proteomics were performed to compare anti-Myc pull-downs from lysates of TbGPI-3Myc expressing and wild type cell lines. TbGPI3-3Myc was the most highly enriched protein in the TbGPI3-3Myc lysate pull-down and the expected partner proteins TbGPI15, TbGPI19, TbGPI2, TbGPI1 and TbERI1 were also identified with significant enrichment. Our proteomics data also suggest that an Arv1-like protein (TbArv1) is a subunit of the T. brucei complex. Yeast and mammalian Arv1 have been previously implicated in GPI biosynthesis, but here we present the first experimental evidence for physical association of Arv1 with GPI biosynthetic machinery. A putative E2-ligase has also been tentatively identified as part of the T. brucei UDP-GlcNAc: PI α1–6 GlcNAc-transferase complex.

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Section: Discussionmentioning

confidence: 88%

Proteomic identification of the UDP-GlcNAc: PI α1–6 GlcNAc-transferase subunits of the glycosylphosphatidylinositol biosynthetic pathway of Trypanosoma brucei

Ji¹,

Tinti²,

Ferguson³

2021

PLoS ONE

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“…[ 4 ] in three related patients, as well as by Segel et al. [ 7 ] in two brothers (see Table 1 and “ Background ” for details). Also interestingly, the latter two brothers revealed DCM, as does our proband, presented here.…”

Section: Discussionmentioning

confidence: 93%

“…Recently, Segel et al. [ 7 ] presented two brothers aged 11 and 18 with the previously described homozygous ARV1 p.G189R missense variant and with severe ID, seizures, and autistic regression. Both these patients had no obvious ophthalmologic abnormalities, showed a milder neurocognitive phenotype compared with the patients with the p.K59_N98del splice mutation, described above, and had dilated cardiomyopathy (DCM), which has not been related to the ARV1 -associated phenotype.…”

Section: Introductionmentioning

confidence: 99%

Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report

et al. 2022

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Background ACAT-related enzyme 2 required for viability 1 (ARV1) encodes a transmembrane lipid transporter of the endoplasmic reticulum, which is presented in all eukaryotes and in plants. Deficiency of ARV1 is clinically presented as autosomal recessive developmental and epileptic encephalopathy 38 (DEE38) in humans and in mice. So far, three different homozygous and two compound heterozygous ARV1 mutations in humans have been reported in 15 children. Case presentation In this case report we present a novel homozygous in-frame ARV1-deletion (c.554_556delTAT, p.L185del) in a 21-year old Caucasian man with developmental delay, intellectual disability, seizures, walking and speech impairments, as well as with a dilated cardiomyopathy (DCM), which has not yet been firmly related to the ARV1-associated phenotype. Interestingly, this novel variant lies in the proximity of the p.G189R mutation, which was previously described in two brothers with DEE38 and dilated cardiomyopathy. Conclusion The finding of dilated cardiomyopathy in the presented as well as in three previously reported patients from two different families indicates that dilated cardiomyopathy is a part of the ARV1-induced DEE38 phenotype. However, more data are needed to make this conclusion definitive.

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“…Six remaining patients were still alive at last follow-up, between age 2 years 5 months and 18 years. [5][6][7][8] Progressive deceleration of head growth is reported in 5 patients and mild-moderate dilated cardiomyopathy in 2. 7 Reported MRI findings include cerebellar atrophy in 3 individuals, delayed myelination in 2, a thin corpus callosum in 1, and a hyperintense signal on T2-weighted with restricted diffusion in the cerebral central tegmental tract in one.…”

Section: Discussionmentioning

confidence: 99%

Migrating Focal Seizures and Myoclonic Status in ARV1- Related Encephalopathy

et al. 2021

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ObjectiveTo report longitudinal clinical, EEG, and MRI findings in 2 sisters carrying compound heterozygous ARV1 mutations and exhibiting a peculiar form of developmental and epileptic encephalopathy (DEE). Neuropathologic features are also described in one of the sisters.MethodsClinical course description, video-EEG polygraphic recordings, brain MRI, skin and muscle biopsies, whole-exome sequencing (WES), and brain neuropathology.ResultsSince their first months of life, both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity. Intractable nonmotor seizures started in both at the eighth month of life, exhibiting the electroclinical characteristics of epilepsy of infancy with migrating focal seizures (EIMFS). In the second year of life, continuous epileptiform EEG activity of extremely high amplitude appeared in association with myoclonic status, leading to severely impaired alertness and responsiveness. Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination. WES identified a compound heterozygous in the ARV1 gene [(p.Ser122Glnfs*7) and (p.Trp163*)] in one patient and was subsequently confirmed in the other. Both sisters died prematurely during respiratory infections. Postmortem neuropathologic examination of the brain, performed in one, revealed atrophic brain changes, mainly involving the cerebellum.ConclusionsThis report confirms that biallelic ARV1 mutations cause a severe form of DEE and adds epilepsy with migrating focal seizures and myoclonic status to the spectrum of epilepsy phenotypes. Considering the potential role of human ARV1 in glycosylphosphatidylinositol (GPI) anchor biosynthesis, this severe syndrome can be assigned to the group of inherited GPI deficiency disorders, with which it shares remarkably similar clinical and neuroimaging features. ARV1 should be considered in the genetic screening of individuals with EIMFS.

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A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures

Cited by 9 publications

References 16 publications

Proteomic identification of the UDP-GlcNAc: PI α1–6 GlcNAc-transferase subunits of the glycosylphosphatidylinositol biosynthetic pathway of Trypanosoma brucei

Proteomic identification of the UDP-GlcNAc: PI α1–6 GlcNAc-transferase subunits of the glycosylphosphatidylinositol biosynthetic pathway of Trypanosoma brucei

Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report

Migrating Focal Seizures and Myoclonic Status in ARV1- Related Encephalopathy

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