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

Molecular Psychiatry volume 9, pages 474–484 (2004)Cite this article

A Corrigendum to this article was published on 22 April 2004

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 test23,24,25,26. Initially, 138 triads of autistic individuals and their parents were tested. Two intronic SNPs (rs1861972 and rs1861973) demonstrated significant association with autism (rs1861972, P=0.0018; rs1861973, P=0.0003; haplotype, P=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=0.0290, rs1861973 P=0.0073, haplotype P=0.0009; broad: rs1861972 P=0.0175, rs1861973 P=0.0107, haplotype P=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.

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Acknowledgements

We thank Cure Autism Now (CAN) and the Autism Genetic Resource Exchange (AGRE) for supplying the resources necessary for this study, Christopher Bartlett for scientific discussions and Emanuel DiCicco-Bloom for critical reading of the paper. We also thank Jay Tischfield and Rutgers University Cell Repository under contract to HBDI for generously providing the AGRE DNA samples. This work was supported in part by research grants from The March of Dimes Birth Defects Foundation (No. 12-FY01-110), National Alliance for Autism Research and The New Jersey Governor's Council of Autism to LMB and March of Dimes Basil O'Connor Starter Research Award (5-FY00-582), NJ Governor's Council for Autism, Whitehall Foundation (2001-12-54-APL), National Ataxia Foundation and National Alliance for Autism Research to JHM. Most importantly, we thank the families who have participated in and contributed to these studies.

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  1. N Gharani and R Benayed: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Genetics, Rutgers University, Piscataway, NJ, USA

    N Gharani, L M Brzustowicz & J H Millonig

  2. Center for Advanced Biotechnology and Medicine, Piscataway, NJ, USA

    R Benayed, V Mancuso & J H Millonig

  3. Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA

    J H Millonig

  4. Department of Psychiatry, UMDNJ-New Jersey Medical School, Piscataway, NJ, USA

    L M Brzustowicz

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Correspondence to J H Millonig.

Appendix

Appendix

Members of the AGRE Consortium

Daniel H Geschwind, University of California at Los Angeles, Los Angeles, USA; Maya Bucan, University of Pennsylvania, Philadephia, USA; W Ted Brown, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA; Joseph Buxbaum, Mt Sinai School of Medicine, New York, USA; Edwin H Cook Jr, University of Chicago, Chicago, USA; T Conrad Gilliam, Columbia Genome Center, New York, USA; David A Greenberg, Mt Sinai Medical Center, New York, USA; David H Ledbetter, University of Chicago, Chicago, USA; Bruce Miller, University of California at San Francisco, San Francisco, USA; Stanley F Nelson, University of California at Los Angeles School of Medicine, Los Angeles, USA; Jonathon Pevsner, Kennedy Kreiger Institute, Baltimore, USA; Jerome I Rotter, Cedar-Sinai Medical Center, Los Angeles, USA; Gerald D Schellenberg, University of Washington, Seattle, USA; Carol A Sprouse, Children's National Medical Center, Baltimore, USA; Rudolph E Tanzi, Massachusetts General Hospital, Boston, USA; Kirk C Wilhelmsen, University of California at San Francisco, San Francisco, USA; and Jeremy M Silverman, Mt Sinai Medical School, New York, USA.

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Gharani, N., Benayed, R., Mancuso, V. et al. Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder. Mol Psychiatry 9, 474–484 (2004). https://doi.org/10.1038/sj.mp.4001498

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