Mutation screening of the neurexin 1 gene in thai patients with intellectual disability and autism spectrum disorder

Abstract

Aim: Neurexin 1 has two major protein isoforms using alternative promoters, coding for the alpha-neurexin 1 (α-NRXN1) and beta-neurexin 1 (β-NRXN1) genes. This study is to explore the possibility that variants of the NRXN1 gene predispose to intellectual disability (ID) and autism spectrum disorder (ASD).

Methods: The coding regions in 24 exons and exon-intron boundaries of the NRXN1 gene were investigated in 115 Thai patients with ID and ASD by direct DNA sequencing.

Results: Nine novel variants of the NRXN1 gene were identified. Four novel variants were found in the β-NRXN1 gene, one variant of six GGC repeats in exon 1, and three variants at the 5'UTR. Five novel variants were identified in the α-NRXN1 gene, four intronic variants and one missense variant in exon 14 (c.2713T>A or p.F905I).

Conclusion: Mutation screening of the NRXN1gene in patients with ID and ASD may be useful to identify potential variants predisposing to ID and ASD. However, further studies utilizing protein functional analysis of the novel variants are required for a more definite conclusion.

FIG. 1.

(a) DNA sequencing shows the nucleotide change of the NRXN1 gene position 2713 from thymine to adenine (c.2713T>A) resulting in alteration of the amino acid from phenylalanine to isoleucine (p.F905I). (b) Alignment of the amino acid at position 905 shows high conservation of the phenylalanine across different species using the PolyPhen-2 program.

FIG. 2.

Summary of the rare missense variants and GGC repeats in the alpha and beta isoforms of the neurexin 1 protein. Figure is not drawn to scale. References: 1, Feng et al. (2006); 2, Kim et al. (2008); 3, Yan et al. (2008); 4, Liu et al. (2012); 5, Gauthier et al. (2011); 6, Camacho-Garcia et al. (2012); *This study (see Supplementary Data S2, Table S2-2 for details). Protein access no: α-neurexin 1, NP_001129131.1; β-neurexin 1, NP_620072.1. SP, signal peptide domain; βN, short beta-neurexin-specific sequence; LNS, laminin/neurexin/sex-hormone-binding protein domain; EGF, epidermal growth-factor-like domain; CH, O-glycosylation sequence; TM, transmembrane domain; PDZ-BD, cytoplasmic domain.