Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder

Dias, Caroline; Punetha, Jaya; Zheng, Céline; Mazaheri, Neda; Rad, Abolfazl; Efthymiou, Stéphanie; Petersen, Andrea; Dehghani, Mohammadreza; Pehlivan, Davut; Partlow, Jennifer N.; Posey, Jennifer E.; Salpietro, Vincenzo; Gezdirici, Alper; Malamiri, Reza Azizi; Menabawy, Nihal M. Al; Selim, Laila; Mehrjardi, Mohammad Yahya Vahidi; Banu, Selina; Polla, Daniel L.; Yang, Edward; Varaghchi, Jamileh Rezazadeh; Mitani, Tadahiro; Beusekom, Ellen van; Najafi, Maryam; Sedaghat, Alireza; Keller‐Ramey, Jennifer; Durham, L. Kathryn; Coban‐Akdemir, Zeynep; Karaca, Ender; Orlova, Valeria V.; Schaeken, Lieke L.M.; Sherafat, Amir; Jhangiani, Shalini N.; Stanley, Valentina; Shariati, Gholamreza; Galehdari, Hamid; Gleeson, Joseph G.; Walsh, Christopher A.; Lupski, James R.; Seiradake, E.; Houlden, Henry; Bokhoven, Hans van; Maroofian, Reza

doi:10.1016/j.ajhg.2019.09.025

Cited by 42 publications

(25 citation statements)

References 36 publications

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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 – 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: Discussionmentioning

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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Section: Discussionmentioning

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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“…Genetic neuromuscular and developmental disorders with onset in the first year of life include a variety of monogenic conditions, including AMC, with expanding clinical differential diagnosis, genetic heterogeneity, and associated disease mechanisms (14)(15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

Neuromuscular and Neuroendocrinological Features Associated With ZC4H2-Related Arthrogryposis Multiplex Congenita in a Sicilian Family: A Case Report

et al. 2021

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Wieacker-Wolff syndrome (WWS) is an X-linked Arthrogryposis Multiplex Congenita (AMC) disorder associated with broad neurodevelopmental impairment. The genetic basis of WWS lies in hemizygous pathogenic variants in ZC4H2, encoding a C4H2 type zinc-finger nuclear factor abundantly expressed in the developing human brain. The main clinical features described in WWS families carrying ZC4H2 pathogenic variants encompass having a short stature, microcephaly, birth respiratory distress, arthrogryposis, hypotonia, distal muscle weakness, and broad neurodevelopmental delay. We hereby report a Sicilian family with a boy clinically diagnosed with WWS and genetically investigated with exome sequencing (ES), leading to the identification of a c.593G>A (p. R198Q) hemizygous pathogenic variant in the ZC4H2 gene. During the first year of life, the onset of central hypoadrenalism led to recurrent hypoglycemic events, which likely contributed to seizure susceptibility. Also, muscle biopsy studies confirmed a pathology of the muscle tissue and revealed peculiar abnormalities of the neuromuscular junction. In conclusion, we expand the phenotypic spectrum of the WWS-related neurodevelopmental disorders and discuss the role of ZC4H2 in the context of the potential neuroendocrinological and neuromuscular features associated with this condition.

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“…Other individuals had targeted neuropathy panel sequencing ( SMN1 , LMNA , MFN2 , MPZ , GJB1 , PMP22 , SH3TC2 , GDAP1 , NEFL , DNAJB2 , HINT ). Exome sequencing and interpretation were carried out as described previously [6–8]. Candidate variants were confirmed by Sanger sequencing.…”

Section: Methodsmentioning

confidence: 99%

Novel variants broaden the phenotypic spectrum of PLEKHG5‐associated neuropathies

Chen

Maroofian

Başak

et al. 2020

Euro J of Neurology

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Background and purpose Pathogenic variants in PLEKHG5 have been reported to date to be causative in three unrelated families with autosomal recessive intermediate Charcot‐Marie‐Tooth disease (CMT) and in one consanguineous family with spinal muscular atrophy (SMA). PLEKHG5 is known to be expressed in the human peripheral nervous system, and previous studies have shown its function in axon terminal autophagy of synaptic vesicles, lending support to its underlying pathogenetic mechanism. Despite this, there is limited knowledge of the clinical and genetic spectrum of disease. Methods We leverage the diagnostic utility of exome and genome sequencing and describe novel biallelic variants in PLEKHG5 in 13 individuals from nine unrelated families originating from four different countries. We compare our phenotypic and genotypic findings with a comprehensive review of cases previously described in the literature. Results We found that patients presented with variable disease severity at different ages of onset (8–25 years). In our cases, weakness usually started proximally, progressing distally, and can be associated with intermediate slow conduction velocities and minor clinical sensory involvement. We report three novel nonsense and four novel missense pathogenic variants associated with these PLEKHG5‐associated neuropathies, which are phenotypically spinal muscular atrophy (SMA) or intermediate Charcot‐Marie‐Tooth disease. Conclusions PLEKHG5‐associated neuropathies should be considered as an important differential in non‐5q SMAs even in the presence of mild sensory impairment and a candidate causative gene for a wide range of hereditary neuropathies. We present this series of cases to further the understanding of the phenotypic and molecular spectrum of PLEKHG5‐associated diseases.

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Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder

Cited by 42 publications

References 36 publications

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

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

Neuromuscular and Neuroendocrinological Features Associated With ZC4H2-Related Arthrogryposis Multiplex Congenita in a Sicilian Family: A Case Report

Novel variants broaden the phenotypic spectrum of PLEKHG5‐associated neuropathies

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