Migratory streams occur throughout the central nervous system (CNS) during development. Neuronal and glial cell populations migrate out of proliferative zones to reach their final location, where neurons soon establish early intercellular connections. Reelin plays a pivotal role in cell migration processes, acting as a stop signal for migrating neurons in several CNS districts, including the neocortex, the cerebellum, and the hindbrain (Rice and Curran, 2001). At the cellular level, Reelin acts by binding to a variety of receptors, including the VLDL receptors, ApoER2, and α3β1 integrins, and also by exerting a proteolytic activity on extracellular matrix proteins, which is critical to neuronal migration (D'Arcangelo et al., 1999; Hiesberger et al., 1999; Quattrocchi et al., 2002). Indeed, neuronal migration is profoundly altered in reeler mice, lacking Reelin protein due to spontaneous deletions of the reelin (RELN) gene (D'Arcangelo et al., 1995). Their brains display major cytoarchitectonic alterations, yielding a behavioral phenotype characterized by action tremor, dystonic posture, and ataxic gait (Goffinet, 1984). Interestingly, despite significant interindividual differences, postmortem studies of brains of autistic patients have consistently found neuropathological evidence of altered neuronal migration, including ectopic neurons, altered cytoarchitectonics, and aberrant fiber tracts, as recently reviewed by Persico and Bourgeron (2006). Furthermore, the RELN gene maps to human chromosome 7q22, in a region hosting one or more autism genes, according to converging evidence from multiple genetic linkage studies (Muhle et al., 2004; Persico and Bourgeron, 2006). These findings provided initial suggestions that Reelin may play relevant roles in neurodevelopmental disorders, such as autism. Yet, autistic patients are not reeler humans: RELN gene mutations resulting in the absence of Reelin protein yield a much more severe phenotype, the Norman-Roberts syndrome (Hong et al., 2000). This rare autosomal recessive neurological disease is characterized by lissencephaly and cerebellar hypoplasia, with severe mental retardation, abnormal neuromuscular connectivity, and congenital lymphedema. Therefore, RELN gene variants potentially conferring genetic liability to neuropsychiatric disorders, such as autism and schizophrenia, were predicted to more likely modulate gene expression levels and/or protein function, rather than to produce a complete loss of function. And indeed, no mutation resulting in premature stop codons and no triplet repeat expansions halting RELN gene expression have been identified to date in autistic or schizophrenic patients. This chapter will thus review current knowledge on RELN gene polymorphisms influencing gene expression and summarize the results of studies addressing the possible genetic association between functional RELN gene variants and autism. Genetic and epigenetic RELN gene variants possibly involved in other neurodevelopmental disorders, such as schizophrenia, will be described elsewhere in this book.
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