A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y

Nguyen, Thien; Wu, Kunwei; Pandey, Saurabh; Lehr, Alexander W.; Li, Yan; Bemben, Michael A.; Badger, John D.; Lauzon, Julie; Wang, Tongguang; Zaghloul, Kareem A.; Thurm, Audrey; Jain, Mahim; Lü, Wei; Roche, Katherine W.

doi:10.1016/j.neuron.2020.03.008

Cited by 62 publications

(45 citation statements)

References 43 publications

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“…Given that there is a homologous gene on the Y chromosome, NLGN4Y , X inactivation escape may be important for dosage compensation between males and females. However, new evidence suggests that NLGN4Y is processed differently than NLGN4X and is not trafficked to the cell surface and does not contribute to the formation of synapses (Nguyen et al, 2020). Thus, any decrease in NLGN4X expression may be deleterious.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization

Kopp

Amarillo

Martinez‐Agosto

et al. 2020

American J of Med Genetics Pt A

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Neuroligin 4 X‐linked (NLGN4X) is an X‐linked postsynaptic scaffolding protein, with functional role in excitatory synapsis development and maintenance, that has been associated with neuropsychiatric disorders such as intellectual disability, autism spectrum disorders (ASD), anxiety, attention deficit hyperactivity disorder (ADHD), and Tourette's syndrome. Chromosomal microarray analysis identified a paternally inherited, 445 Kb deletion on Xp22.3 that includes the entire NLGN4X in a 2.5 year old female (46,XX) with congenital hypotonia, strabismus, ASD, and increased aggressive behavioral issues. Her family history is significant for a mother with learning disabilities, a father with anxiety, major depressive disorder, and substance abuse, as well as two maternal half‐brothers with developmental delays. X‐inactivation studies in the proband's blood showed random X‐inactivation despite the presence of an abnormal X chromosome. Furthermore, trio exome sequencing did not reveal any other deleterious variant that could explain her phenotype. Our report describes the first example of a paternally inherited NLGN4X microdeletion as the genetic etiology of ASD in a female proband, and the psychiatric phenotypes in the father. It also provides further evidence that NLGN4X is sensitive to dosage changes in females, and can contribute to a variety of psychiatric features within the same family.

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Section: Discussionmentioning

confidence: 99%

Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization

Kopp

Amarillo

Martinez‐Agosto

et al. 2020

American J of Med Genetics Pt A

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“…What is the function of NLGN4Y if it cannot get to the surface? Nguyen et al (2020) demonstrated that NLGN4Y can oligomerize with NLGN1, 2, 3, and 4X and reduce their surface trafficking. In addition, exogenously expressed NLGN4Y on a WT background decreased mEPSCs suggesting NLGN4Y acts to inhibit NLGN1-3 function.…”

Section: Nlgn4x and Nlgn4ymentioning

confidence: 99%

“…To explore the function of NLGN4Y, in a recent study, we directly compared NLGN4X and NLGN4Y and found that NLGN4Y cannot traffic to the surface to induce synapses (Nguyen et al, 2020). Furthermore, the differential trafficking observed between NLGN4X and NLGN4Y is due to an amino acid difference at position 93, with proline for NLGN4X and serine for NLGN4Y.…”

Section: Nlgn4x and Nlgn4ymentioning

confidence: 99%

“…It is puzzling why a variant that failed to induce synaptogenesis on a null background can still enhance synaptic function. Interestingly, a cluster of NLGN4X-associated variants has been identified near the NLGN4X R87W that also display a deficit in surface expression ( Nguyen et al, 2020 ). Because these NLGN4X-associated variants are in the ECD, it is of interest to investigate their ability to bind to neurexin.…”

Section: Nlgn4x and Asd/idmentioning

confidence: 99%

“…NLGN4X and NLGN4Y were historically grouped together and assumed to have the same function due to their almost identical sequence identity. However, recent findings show that a single amino acid difference in NLGN4Y results in a trafficking deficit leading to decreased surface expression and synaptic function (Nguyen et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Neuroligins and Neurodevelopmental Disorders: X-Linked Genetics

Nguyen

Lehr

Roche

2020

Front. Synaptic Neurosci.

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder that results in socialcommunication impairments, as well as restricted and repetitive behaviors. Moreover, ASD is more prevalent in males, with a male to female ratio of 4 to 1. Although the underlying etiology of ASD is generally unknown, recent advances in genome sequencing have facilitated the identification of a host of associated genes. Among these, synaptic proteins such as cell adhesion molecules have been strongly linked with ASD. Interestingly, many large genome sequencing studies exclude sex chromosomes, which leads to a shift in focus toward autosomal genes as targets for ASD research. However, there are many genes on the X chromosome that encode synaptic proteins, including strong candidate genes. Here, we review findings regarding two members of the neuroligin (NLGN) family of postsynaptic adhesion molecules, NLGN3 and NLGN4. Neuroligins have multiple isoforms (NLGN1-4), which are both autosomal and sexlinked. The sex-linked genes, NLGN3 and NLGN4, are both on the X chromosome and were among the first few genes to be linked with ASD and intellectual disability (ID). In addition, there is a less studied human neuroligin on the Y chromosome, NLGN4Y, which forms an X-Y pair with NLGN4X. We will discuss recent findings of these neuroligin isoforms regarding function at the synapse in both rodent models and human-derived differentiated neurons, and highlight the exciting challenges moving forward to a better understanding of ASD/ID.

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Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

et al. 2021

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The X‐linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild‐type and mutated forms of PTCHD1‐GFP in HEK 293T and in Neuro‐2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD.

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A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y

Cited by 62 publications

References 43 publications

Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization

Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization

Neuroligins and Neurodevelopmental Disorders: X-Linked Genetics

Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

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