A Substitution Involving the NLGN4 Gene Associated with Autistic Behavior in the Greek Population

Abstract

Autism is a neurodevelopmental disorder characterized by clinical, etiologic, and genetic heterogeneity. During the last decade, predisposing genes and genetic loci were under investigation. Recently, mutations in two X-linked neuroligin genes, neuroligin 3 (NLGN3) and neuroligin 4 (NLGN4), have been implicated in the pathogenesis of autism. In our ongoing survey, we screened 169 patients with autism for mutations linked with autism. In the preliminary study of specific exons of NLGN3 and NLGN4 genes, we identified the p.K378R substitution (c.1597 A > G) in exon 5 of the NLGN4 gene in a patient who was found to have mild autism and normal IQ at 3 years of age. The same mutation has previously been found in a patient with autism. It is important that, for the first time, a specific mutation in neuroligins is confirmed in a molecular screen in another homogeneous ethnic population. This finding further contributes to consideration of neuroligins as probable candidate genes for future molecular genetic studies, suggesting that a defect of synaptogenesis may predispose to autism.

The genomically mosaic brain: Aneuploidy and more in neural diversity and disease

“…To examine this model, a recent study of families with autistic children from the Autism Genetic Resource Exchange [227] provided evidence that the chromosomal region Xp22.11-p21.2 is linked with an autism predisposition, but inheritance through dominant transmission remains unclear [228]. Proposed gene candidates in this region include the interleukin 1 receptor accessory protein-like gene ( IL1RAPL1 ), which is thought to be involved in neurotransmitter release and synaptic plasticity [228]; other ASD candidates on chromosome X are two neuroligin genes that aid in synapse formation, NLGN3 and NLGN4X , both of which have been associated with autistic behavior [229]. Even with implicated chromosomal regions and potential gene candidates, the etiology of ASD largely remains a mystery.…”

SHANK1 and autism spectrum disorders

“…Twin and family studies indicate that genetic factors play an important role in the etiology of autism with the heritability estimate more than 90% [2,3]. Though the causes of ASD are largely unknown, neurexin-neuroligin-shank (NRXN-NLGN-SHANK) pathway genes mutations have been implicated in ASD [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. NLGN proteins, expressed highly in the brain, are postsynaptic adhesion molecules interacting with presynaptic NRXNs [9].…”

The complex genetics in autism spectrum disorders

“…Multiple genetic changes in Nrxn [84][85][86][87][88][89][90][91][92][93][94] and Nlgn genes [92,93,[95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110] have been found in ASD patients. These changes include (i) point mutations, which cause frame shifts, small deletions, and missense mutations in both coding and promoter regions, (ii) distinct translocation events, and (iii) large-scale deletions of chromosomal DNA containing these gene loci.…”