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PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder / J. PIJUAN in Autism Research, 14-6 (June 2021)
[article]
Titre : PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : J. PIJUAN, Auteur ; J. D. ORTIGOZA-ESCOBAR, Auteur ; J. ORTIZ, Auteur ; A. ALCALÁ, Auteur ; M. J. CALVO, Auteur ; M. CUBELLS, Auteur ; C. HERNANDO-DAVALILLO, Auteur ; F. PALAU, Auteur ; J. HOENICKA, Auteur Article en page(s) : p.1088-1100 Langues : Anglais (eng) Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics Autism Spectrum Disorder/genetics DNA Copy Number Variations Exome Genetic Predisposition to Disease/genetics Humans Nerve Tissue Proteins/genetics Receptors, Cell Surface Lrrc40 Plxna2 autism spectrum disorder diagnosis neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. En ligne : http://dx.doi.org/10.1002/aur.2502 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449
in Autism Research > 14-6 (June 2021) . - p.1088-1100[article] PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder [Texte imprimé et/ou numérique] / J. PIJUAN, Auteur ; J. D. ORTIGOZA-ESCOBAR, Auteur ; J. ORTIZ, Auteur ; A. ALCALÁ, Auteur ; M. J. CALVO, Auteur ; M. CUBELLS, Auteur ; C. HERNANDO-DAVALILLO, Auteur ; F. PALAU, Auteur ; J. HOENICKA, Auteur . - p.1088-1100.
Langues : Anglais (eng)
in Autism Research > 14-6 (June 2021) . - p.1088-1100
Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics Autism Spectrum Disorder/genetics DNA Copy Number Variations Exome Genetic Predisposition to Disease/genetics Humans Nerve Tissue Proteins/genetics Receptors, Cell Surface Lrrc40 Plxna2 autism spectrum disorder diagnosis neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. En ligne : http://dx.doi.org/10.1002/aur.2502 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449