Not all neuroligin 3 and 4X missense variants lead to significant functional inactivation

Xu, Xiaojuan; Hu, Zhengmao; Zhang, Lusi; Liu, Hongfang; Cheng, Yuemei; Xia, Kun; Zhang, Xuehong

doi:10.1002/brb3.793

Cited by 6 publications

(7 citation statements)

References 20 publications

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“…However, a fraction of NLGN4 mutations also include single nucleotide polymorphisms creating missense variants of relatively unknown physiological consequence. Earlier studies indicate that while some of these missense mutations do exhibit pathogenic phenotypes, other variants may not lead to significant functional inactivation (Xu et al, 2017). In this study, we describe a severely autistic patient carrying a single amino acid substitution (i.e., R101Q) in NLGN4 (Figs.…”

Section: Discussionmentioning

confidence: 86%

“…Interestingly, the R101Q mutation is also situated next to a region with multiple previously identified ASD mutations (e.g., G84R, R87W, and G99S), some with mostly unknown mechanistic consequences (Fig. 1C; Fabrichny et al, 2007;Zhang et al, 2009;Xu et al, 2017;Schepici et al, 2019;Nguyen et al, 2020). A structural model of the extracellular domain of NLGN4 predicted that the R101Q mutation is spatially oriented opposite to its dimerization domain and away from its NRXN contact site (Fig.…”

Section: Autistic Individual Carries a Missense Mutation In Nlgn4mentioning

confidence: 87%

“…However, a number of ASD patients also carry NLGN4 missense mutations with relatively unknown pathologic consequences (Fabrichny et al, 2007;Schepici et al, 2019). Although some of these amino acid substitutions have been shown to disrupt the structural integrity of NLGN4 (e.g., R87W; Zhang et al, 2009) or enhance its binding affinity for synaptic receptors (e.g., R704; Chanda et al, 2016;Marro et al, 2019), other variants might simply represent genetic polymorphisms without any functional significance (e.g., G84R, G99S, Q162K, A283T; Fabrichny et al, 2007;Xu et al, 2017). Therefore, it remained unclear whether there are other pathogenic mechanisms by which point mutations can affect NLGN4 properties and impair synapse function in ASD.…”

Section: Introductionmentioning

confidence: 99%

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An Autism-Associated Mutation Impairs Neuroligin-4 Glycosylation and Enhances Excitatory Synaptic Transmission in Human Neurons

et al. 2020

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Neuroligins (NLGNs) are a class of postsynaptic cell adhesion molecules that interact with presynaptic neurexins (NRXNs) and regulate synapse function. NLGN4 is a member of the NLGN family and consists of a unique amino acid sequence in humans that is not evolutionarily well conserved in rodents. The human-specific NLGN4 gene has been reported to be mutated in many patients with autism and other neurodevelopmental disorders. However, it remained unclear how these mutations might alter the molecular properties of NLGN4 and affect synaptic transmission in human neurons. Here, we describe a severely autistic male patient carrying a single amino acid substitution (R101Q) in the NLGN4 gene. When expressed in HEK293 cells, the R101Q mutation in NLGN4 did not affect its binding affinity for NRXNs or its capacity to form homodimers. This mutation, however, impaired the maturation of NLGN4 protein by inhibiting N-linked glycosylation at an adjacent residue (N102), which is conserved in all NLGNs. As a result, the R101Q substitution significantly decreased the surface trafficking of NLGN4 and increased its retention in the endoplasmic reticulum and Golgi apparatus. In human neurons derived from male stem cell lines, the R101Q mutation also similarly reduced the synaptic localization of NLGN4, resulting in a loss-of-function phenotype. This mutation-induced trafficking defect substantially diminished the ability of NLGN4 to form excitatory synapses and modulate their functional properties. Viewed together, our findings suggest that the R101Q mutation is pathogenic for NLGN4 and can lead to synaptic dysfunction in autism.

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Section: Discussionmentioning

confidence: 86%

Section: Autistic Individual Carries a Missense Mutation In Nlgn4mentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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An Autism-Associated Mutation Impairs Neuroligin-4 Glycosylation and Enhances Excitatory Synaptic Transmission in Human Neurons

et al. 2020

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“…Substitutions G84R, Q162K and A283T have also been described for NLGN4X . Despite in silico prediction of damaging effects, they do not alter NLGN4X levels, localization and ability to bind NRXNβ1 (Xu et al, 2017).…”

Section: Loss or Gain Of Function?mentioning

confidence: 85%

The neuroligins and the synaptic pathway in Autism Spectrum Disorder

Trobiani

Meringolo

Diamanti

et al. 2020

Neuroscience & Biobehavioral Reviews

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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“…These studies screened cohorts of very different geographical origins but failed to identify promising nonsynonymous variant in NLGN3 (Talebizadeh et al, ; Avdjieva‐Tzavella et al, ; Blasi et al, ; Gauthier et al, ; Mikhailov et al, ; Pampanos et al, ; Steinberg et al, ; ; Vincent et al, ; Volaki et al, ; Wermter, Kamp‐Becker, Strauch, Schulte‐Körne, & Remschmidt, ; Xu et al, ; Yanagi et al, ; Ylisaukko‐oja et al, ). The screening of a Chinese cohort identified a novel missense variant Gly406Ser (Xu et al, ), but functional studies performed recently could not identify any functional consequences on NLGN3 function (Xu et al, ). Another missense variant was identified by WES performed in a cohort of simplex and multiplex families with ASD, in one boy with ID, hyperactivity and dysmorphic features (c.1022T>C, Val341Ala), but the authors did not reach a conclusion about its pathogenicity as no functional validation was performed (Yu, Coulter, Okamura‐Ikeda, & Walsh, ).…”

Section: Resultsmentioning

confidence: 99%

Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment

Quartier

Courraud

et al. 2019

Human Mutation

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The X‐linked NLGN3 gene, encoding a postsynaptic cell adhesion molecule, was involved in a nonsyndromic monogenic form of autism spectrum disorder (ASD) by the description of one unique missense variant, p.Arg451Cys (Jamain et al. 2003). We investigated here the pathogenicity of additional missense variants identified in two multiplex families with intellectual disability (ID) and ASD: c.1789C>T, p.Arg597Trp, previously reported by our group (Redin et al. 2014) and present in three affected cousins and c.1540C>T, p.Pro514Ser, identified in two affected brothers. Overexpression experiments in HEK293 and HeLa cell lines revealed that both variants affect the level of the mature NLGN3 protein, its localization at the plasma membrane and its presence as a cleaved form in the extracellular environment, even more drastically than what was reported for the initial p.Arg451Cys mutation. The variants also induced an unfolded protein response, probably due to the retention of immature NLGN3 proteins in the endoplasmic reticulum. In comparison, the c.1894A>G, p.Ala632Thr and c.1022T>C, p.Val341Ala variants, present in males from the general population, have no effect. Our report of two missense variants affecting the normal localization of NLGN3 in a total of five affected individuals reinforces the involvement of the NLGN3 gene in a neurodevelopmental disorder characterized by ID and ASD.

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Not all neuroligin 3 and 4X missense variants lead to significant functional inactivation

Cited by 6 publications

References 20 publications

An Autism-Associated Mutation Impairs Neuroligin-4 Glycosylation and Enhances Excitatory Synaptic Transmission in Human Neurons

An Autism-Associated Mutation Impairs Neuroligin-4 Glycosylation and Enhances Excitatory Synaptic Transmission in Human Neurons

The neuroligins and the synaptic pathway in Autism Spectrum Disorder

Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment

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