Netrin‐G2 dysfunction causes a Rett‐like phenotype with areflexia

Heimer, Gali; Woerden, Geeske M. van; Barel, Ortal; Marek‐Yagel, Dina; Kol, Nitzan; Munting, Johannes B.; Borghei, Minoeshka; Atawneh, Osama M.; Nissenkorn, Andreea; Rechavi, Gideon; Anikster, Yair; Elgersma, Ype; Kushner, Steven A.; Zeev, Bruria Ben

doi:10.1002/humu.23945

Cited by 11 publications

(7 citation statements)

References 65 publications

(104 reference statements)

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“…Among GPI-APs potentially decreased in PIGG-defective neuronal cells, is NTNG2, which is deeply dependent upon PIGG (Figure 8). Recently, loss-of-function mutations in NTNG2, which is selectively expressed in presynaptic region, were found in several families, whose homozygous members showed global developmental delay, severe intellectual disability, muscle weakness, and behavioral abnormalities like Rett syndrome (46, 47). All these symptoms overlap with those of PIGG -IGD (20, 37).…”

Section: Discussionmentioning

confidence: 99%

Ethanolamine-phosphate on the second mannose is the preferential bridge for some of the brain GPI-anchored proteins

Ishida

Maki

Ninomiya

et al. 2020

Preprint

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Glycosylphosphatidylinositols (GPIs) are glycolipids that anchor many proteins (GPI-APs) on the cell surface. GPI precursor has three mannoses, which in mammalian cells, are all modified by the addition of ethanolamine-phosphate (EthN-P). It is postulated that EthN-P on the third mannose (EthN-P-Man3) is the bridge between GPI to the protein and the second (EthN-P-Man2) is removed after GPI-protein attachment. However, EthN-P-Man2 may not be always transient as postulated, as mutations of PIGG, the enzyme that transfers EthN-P to Man2, result in inherited GPI deficiencies (IGDs), characterized by neuronal dysfunctions. We hypothesized that EthN-P-Man2 plays a role beyond what is now postulated. Indeed, EthN-P on Man2 is not only the alternate bridge in some GPI-APs but the actual bridge in others, among them, the ect-5’-nucleotidase and netrin G2. We found that CD59, a GPI-AP, is attached via EthN-P-Man2 in both PIGB-knockout cells, in which GPI lacks Man3 and with a small fraction, in wild type cells. Our findings modify the current view of GPI anchoring and provide mechanistic bases of IGDs caused by PIGG mutations.

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Section: Discussionmentioning

confidence: 99%

Ethanolamine-phosphate on the second mannose is the preferential bridge for some of the brain GPI-anchored proteins

Ishida

Maki

Ninomiya

et al. 2020

Preprint

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“…NTNG2, a gene that encodes Netrin-G2, is required for proper axonal guidance during early brain development and synaptic transmission [69]. Several mutations in NTNG2 have been described and they cause global developmental delay, hypotonia, secondary microcephaly, Rett-like phenotype, and autistic features [70][71][72]. Knockdown of murine Ntng2 caused severe impairments of neuronal morphology and cortical migration [71] while knockout of Ntng2 in a cellular model resulted in short neurites [72].…”

Section: Serbp1 As a New Regulator Of Cancer Metabolismmentioning

confidence: 99%

The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation

Kosti

Araújo

et al. 2020

Genome Biol

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Background: RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth. Identification and characterization of oncogenic RBPs and their regulatory networks provide new opportunities for targeted therapy. Results: We identify the RNA-binding protein SERBP1 as a novel regulator of glioblastoma (GBM) development. High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo-and radiotherapy. SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines. RNAcompete identifies a GC-rich region as SERBP1-binding motif; subsequent genomic and functional analyses establish SERBP1 regulation role in metabolic routes preferentially used by cancer cells. An important consequence of these functions is SERBP1 impact on methionine production. SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function. Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites. Conclusions: SERBP1 is the first example of an RNA-binding protein functioning as a central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. By bridging these two processes, SERBP1 enhances glioma stem cell phenotypes and contributes to GBM poorly differentiated state.

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“…We assessed the effect of the SNRPN variant on protein function and its pathogenicity using our in-house developed functional genomics screen "Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations (PRiSM)" (for other studies where this has been used see [29][30][31][32]).…”

Section: Prism Screenmentioning

confidence: 99%

The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature

Pellikaan

Woerden

Kleinendorst

et al. 2021

Genes

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Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader–Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C>T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the ‘Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations’ (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype–phenotype relationship in PWS.

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Netrin‐G2 dysfunction causes a Rett‐like phenotype with areflexia

Cited by 11 publications

References 65 publications

Ethanolamine-phosphate on the second mannose is the preferential bridge for some of the brain GPI-anchored proteins

Ethanolamine-phosphate on the second mannose is the preferential bridge for some of the brain GPI-anchored proteins

The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation

The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature

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