Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder

Abstract

Mouse mutants of the homeobox transcription factor Engrailed2 (En2) and autistic individuals display similar cerebellar morphological abnormalities, which include hypoplasia and a decrease in the number of Purkinje cells. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Human EN2 maps to 7q36, a chromosomal region that has demonstrated suggestive linkage to autism spectrum disorder (ASD). [20][21][22] To investigate EN2 for evidence of association with ASD, four single-nucleotide polymorphisms (SNPs) (rs3735653, rs1861972, rs1861973, rs2361689) that span the majority of the 8.0 kb gene were assessed by the transmission/disequilibrium test [23][24][25][26] . Initially, 138 triads of autistic individuals and their parents were tested. Two intronic SNPs (rs1861972 and rs1861973) demonstrated significant association with autism (rs1861972, P ¼ 0.0018; rs1861973, P ¼ 0.0003; haplotype, P ¼ 0.000005). Flanking exonic SNPs (rs3735653 and rs2361689) did not display association. This analysis was then extended to include 167 small nuclear ASD pedigrees and significant association was again only observed for rs1861972 and rs1861973 under both the narrow and broad diagnostic criteria (narrow: rs1861972 P ¼ 0.0290, rs1861973 P ¼ 0.0073, haplotype P ¼ 0.0009; broad: rs1861972 P ¼ 0.0175, rs1861973 P ¼ 0.0107, haplotype P ¼ 0.0024). These data demonstrate association between a cerebellar patterning gene and ASD, suggesting a role for EN2 as a susceptibility locus and supporting a neurodevelopmental defect hypothesis in the etiology of autism.

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…195 An association of the intronic haplotype AC of rs1861972 and rs1861973 has been replicated in two different sub-samples of the AGRE consortium and one National Institute of Mental Health (NIMH) sample. 191,192 The exonic SNP rs3735653 consistently did not show association with AD in two studies 192,194 similar to other assessed exonic variants. 191 The latter study additionally assessed the effects of EN2 expression in cultures of primary neuronal precursor cells obtained from a rat cerebral cortex and found reduced neuronal differentiation in cells showing misexpression of EN2.…”

“…[191][192][193][194] EN2 is a homeobox transcription factor that plays a role during cerebellar and brainstem development.…”

The ups and downs of Wnt signaling in prevalent neurological disorders

“…Previous studies found an association of a PvuII restriction fragment length polymorphism located in the 5 0 UTR region of EN2 in 100 autistic children and 100 control children (Petit et al, 1995). More recently, in a large number of nuclear families it was demonstrated that two intronic SNPs (SNP id: rs1861972 and rs1861973) were highly associated with the autistic phenotype, both in single locus tests as well as in haplotype analysis (Gharani et al, 2004;Benayed et al, 2005). Homozygous null mutants for En-2 in mouse display abnormal foliation patterns in the posterior half of the cerebellum and changes in Purkinje and granule cells in some posterior folia (Joyner et al, 1991;Millen et al, 1994;Vogel et al, 1996).…”

“…Currently, few studies on candidate genes which converge on linkage signals have been consistently associated with autism (Folstein and Rosen-Sheidley, 2001;Bartlett et al, 2005). Among them, and within a widely confirmed linkage region in the long arm of chromosome 7, recent evidence has shown that Wnt2 and Engrailed 2 (EN2), a Wnt/b-catenin target gene (McGrew et al, 1999), may be genetically associated with autism (Petit et al, 1995;Wassink et al, 2001;McCoy et al, 2002;Zhong et al, 2003;Gharani et al, 2004;Benayed et al, 2005).…”

“…At present, several polymorphisms in exons as well as introns and regulatory regions of the EN2 gene have been genotyped in different autistic samples including families coming from the Autism Genetic Resource Exchange (AGRE) initiative as well as to the NIMH Center for Collaborative Genetic Studies (Petit et al, 1995;Zhong et al, 2003;Gharani et al, 2004;Benayed et al, 2005). Previous studies found an association of a PvuII restriction fragment length polymorphism located in the 5 0 UTR region of EN2 in 100 autistic children and 100 control children (Petit et al, 1995).…”