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Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder

Abstract

Autistic disorder (MIM 209850) is currently viewed as a neurodevelopmental disease. Reelin plays a pivotal role in the development of laminar structures including the cerebral cortex, hippocampus, cerebellum and of several brainstem nuclei. Neuroanatomical evidence is consistent with Reelin involvement in autistic disorder. In this study, we describe several polymorphisms identified using RNA-SSCP and DNA sequencing. Association and linkage were assessed comparing 95 Italian patients to 186 ethnically-matched controls, and using the transmission/disequilibrium test and haplotype-based haplotype relative risk in 172 complete trios from 165 families collected in Italy and in the USA. Both case-control and family-based analyses yield a significant association between autistic disorder and a polymorphic GGC repeat located immediately 5′ of the reelin gene (RELN) ATG initiator codon, as well as with specific haplotypes formed by this polymorphism with two single-base substitutions located in a splice junction in exon 6 and within exon 50. Triplet repeats located in 5′ untranslated regions (5′UTRs) are indicative of strong transcriptional regulation. Our findings suggest that longer triplet repeats in the 5′UTR of the RELN gene confer vulnerability to autistic disorder.

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Acknowledgements

The authors are very grateful to all families who participated in this study. We also wish to acknowledge Riccardo Adriani, Daniela Conciatori, David J Vandenbergh, Paola Vannini, and Rossella Ventura for their collaboration, Udaya DeSilva and Eric D Green for providing the human reelin cDNA clones, Jeffrey C Long for the 3LOCUS program, Jurg Ott for statistical advice and Raymond R Crowe, André M Goffinet, Joseph Piven and Steven S Smith for reviewing the manuscript.

This work was supported by grant BMH4-CT96-0730 from the European Community Biomed-2 Program, grant E.0858 from Telethon-Italy, grant 99.00555.PF33 from Consiglio Nazionale delle Ricerche, and by grants from Fondazione CARISAL (Salerno, Italy), from the Italian Association of Parents of Autistic Subjects (ANGSA) and from the National Alliance for Autism Research (Princeton, NJ, USA).

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Persico, A., D'Agruma, L., Maiorano, N. et al. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry 6, 150–159 (2001). https://doi.org/10.1038/sj.mp.4000850

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  • DOI: https://doi.org/10.1038/sj.mp.4000850

Keywords

  • allelic association
  • autism
  • cranial circumference
  • haplotype relative risk
  • linkage disequilibrium
  • reeler mouse
  • serotonin
  • splice junction
  • transmission/disequilibrium test
  • trinucleotide repeat

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