NRXN3 mutations cause developmental delay, movement disorder, and behavioral problems: CRISPR edited cells based WES results

Kamal, Neda; Khamirani, Hossein Jafari; Dara, Mahintaj; Dianatpour, Mehdi

doi:10.1016/j.gene.2023.147347

Cited by 4 publications

(4 citation statements)

References 25 publications

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“…Neurexins are cell-surface receptors for neuroligins to form a transsynaptic complex involved in synaptic junction and neurotransmission that have often been reported as implicated in neuropsychiatric disorders, especially ASD [ 41 ]. The phenotype of patients with neurexin-III deficiency may include developmental delay or learning impairment, movement disorder, and behavioral problems [ 42 ]. NRXN3 has already been proposed as a candidate gene in GTS linkage studies [ 43 ], and its deletions have been found in ASD [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Structural Variants and Implicated Processes Associated with Familial Tourette Syndrome

Fichna,

Chiliński,

Halder

et al. 2024

IJMS

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Gilles de la Tourette syndrome (GTS) is a neurodevelopmental psychiatric disorder with complex and elusive etiology with a significant role of genetic factors. The aim of this study was to identify structural variants that could be associated with familial GTS. The study group comprised 17 multiplex families with 80 patients. Structural variants were identified from whole-genome sequencing data and followed by co-segregation and bioinformatic analyses. The localization of these variants was used to select candidate genes and create gene sets, which were subsequently processed in gene ontology and pathway enrichment analysis. Seventy putative pathogenic variants shared among affected individuals within one family but not present in the control group were identified. Only four private or rare deletions were exonic in LDLRAD4, B2M, USH2A, and ZNF765 genes. Notably, the USH2A gene is involved in cochlear development and sensory perception of sound, a process that was associated previously with familial GTS. In addition, two rare variants and three not present in the control group were co-segregating with the disease in two families, and uncommon insertions in GOLM1 and DISC1 were co-segregating in three families each. Enrichment analysis showed that identified structural variants affected synaptic vesicle endocytosis, cell leading-edge organization, and signaling for neurite outgrowth. The results further support the involvement of the regulation of neurotransmission, neuronal migration, and sound-sensing in GTS.

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Section: Discussionmentioning

confidence: 99%

Structural Variants and Implicated Processes Associated with Familial Tourette Syndrome

Fichna,

Chiliński,

Halder

et al. 2024

IJMS

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“…Finally, eicosa-11,14,17-trienoic acid associated with rs2370981 mapped to NRXN3 (neurexin 3) belongs to the long-chain fatty acids, with very few articles published on eicosa-11,14,17-trienoic acid [ 28 ]. NRXN3 encodes the receptor and cell adhesion molecules mainly involved in the nervous system [ 29 ]. Therefore, most mutations in this gene have been reported in neurological diseases, and several associations with carcinoma have been reported, albeit not in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Non-invasive biomarkers for early diagnosis of pancreatic cancer risk: metabolite genomewide association study based on the KCPS-II cohort

Han,

Jung,

Kim

et al. 2023

J Transl Med

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Background Pancreatic cancer is a lethal disease with a high mortality rate. The difficulty of early diagnosis is one of its primary causes. Therefore, we aimed to discover non-invasive biomarkers that facilitate the early diagnosis of pancreatic cancer risk. Methods The study subjects were randomly selected from the Korean Cancer Prevention Study-II and matched by age, sex, and blood collection point [pancreatic cancer incidence (n = 128) vs. control (n = 256)]. The baseline serum samples were analyzed by non-targeted metabolomics, and XGBoost was used to select significant metabolites related to pancreatic cancer incidence. Genomewide association study for the selected metabolites discovered valuable single nucleotide polymorphisms (SNPs). Moderation and mediation analysis were conducted to explore the variables related to pancreatic cancer risk. Results Eleven discriminant metabolites were selected by applying a cut-off of 4.0 in XGBoost. Five SNP presented significance in metabolite-GWAS (p ≤ 5 × 10–6) and logistic regression analysis. Among them, the pair metabolite of rs2370981, rs55870181, and rs72805402 displayed a different network pattern with clinical/biochemical indicators on comparison with allelic carrier and non-carrier. In addition, we demonstrated the indirect effect of rs59519100 on pancreatic cancer risk mediated by γ-glutamyl tyrosine, which affects the smoking status. The predictive ability for pancreatic cancer on the model using five SNPs and four pair metabolites with the conventional risk factors was the highest (AUC: 0.738 [0.661–0.815]). Conclusions Signatures involving metabolites and SNPs discovered in the present research may be closely associated with the pathogenesis of pancreatic cancer and for use as predictive biomarkers allowing early pancreatic cancer diagnosis and therapy.

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“…Additionally, a microdeletion of 7177 base pairs (79176037–79183213) affecting NRXN3 was detected in four patients; two of them were sisters in a Saudi epilepsy cohort [ 66 ]. Furthermore, two Iranian families were described with homozygous and compound heterozygous variants characterized by learning disabilities, developmental delays, an inability to walk, and behavioral problems [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Case Report—An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions

Feichtinger

Preisel

Brugger

et al. 2023

Genes

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Background: Heterozygous, large-scale deletions at 14q24.3-31.1 affecting the neurexin-3 gene have been associated with neurodevelopmental disorders such as autism. Both “de novo” occurrences and inheritance from a healthy parent suggest incomplete penetrance and expressivity, especially in autism spectrum disorder. NRXN3 encodes neurexin-3, a neuronal cell surface protein involved in cell recognition and adhesion, as well as mediating intracellular signaling. NRXN3 is expressed in two distinct isoforms (alpha and beta) generated by alternative promoters and splicing. MM/Results: Using exome sequencing, we identified a monoallelic frameshift variant c.159_160del (p.Gln54AlafsTer50) in the NRXN3 beta isoform (NM_001272020.2) in a 5-year-old girl with developmental delay, autism spectrum disorder, and behavioral issues. This variant was inherited from her mother, who did not have any medical complaints. Discussion: This is the first detailed report of a loss-of-function variant in NRXN3 causing an identical phenotype, as reported for heterozygous large-scale deletions in the same genomic region, thereby confirming NRXN3 as a novel gene for neurodevelopmental disorders with autism.

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NRXN3 mutations cause developmental delay, movement disorder, and behavioral problems: CRISPR edited cells based WES results

Cited by 4 publications

References 25 publications

Structural Variants and Implicated Processes Associated with Familial Tourette Syndrome

Structural Variants and Implicated Processes Associated with Familial Tourette Syndrome

Non-invasive biomarkers for early diagnosis of pancreatic cancer risk: metabolite genomewide association study based on the KCPS-II cohort

Case Report—An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions

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