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

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.

[1]  T. Oakland,et al.  A Review of the Vineland Adaptive Behavior Scales, Survey Form , 1985 .

[2]  A. Goffinet.  Events governing organization of postmigratory neurons: Studies on brain development in normal and reeler mice , 1984, Brain Research Reviews.

[3]  P. Teitelbaum,et al.  Movement analysis in infancy may be useful for early diagnosis of autism. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[4]  S. Folstein,et al.  An autosomal genomic screen for autism. Collaborative linkage study of autism. , 1999, American journal of medical genetics.

[5]  Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. , 1991 .

[6]  K. Grotemeyer,et al.  Serotonin and amino acid content in platelets of autistic children , 1993, Acta psychiatrica Scandinavica.

[7]  P. Gasparini,et al.  Development of RNA‐SSCP protocols for the identification and screening of CFTR mutations: Identification of two new mutations , 1994, Human mutation.

[8]  N. Minshew,et al.  Oculomotor evidence for neocortical systems but not cerebellar dysfunction in autism , 1999, Neurology.

[9]  William D. Dupont,et al.  Power and sample size calculations. A review and computer program. , 1990, Controlled clinical trials.

[10]  T. Curran,et al.  Detection of the reelin breakpoint in reeler mice. , 1996, Brain research. Molecular brain research.

[11]  A. Ciaranello,et al.  The Neurobiology of Infantile Autism , 1995, Annual review of neuroscience.

[12]  J. Terwilliger,et al.  A haplotype-based 'haplotype relative risk' approach to detecting allelic associations. , 1992, Human heredity.

[13]  I. Rapin.  Autism in search of a home in the brain , 1999, Neurology.

[14]  W. Grove.  Statistical Methods for Rates and Proportions, 2nd ed , 1981 .

[15]  A. Couteur,et al.  Autism diagnostic interview: A standardized investigator-based instrument , 1989, Journal of autism and developmental disorders.

[16]  M. Rutter.  Genetic Studies of Autism: From the 1970s into the Millennium , 2000, Journal of abnormal child psychology.

[17]  D. Curtis,et al.  Monte Carlo tests for associations between disease and alleles at highly polymorphic loci , 1995, Annals of human genetics.

[18]  J. Nurnberger,et al.  A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. , 1991, Nucleic acids research.

[19]  D A Krug,et al.  Behavior checklist for identifying severely handicapped individuals with high levels of autistic behavior. , 1980, Journal of child psychology and psychiatry, and allied disciplines.

[20]  P. Rodier,et al.  Embryological origin for autism: Developmental anomalies of the cranial nerve motor nuclei , 1996, The Journal of comparative neurology.

[21]  E. Green,et al.  The human reelin gene: isolation, sequencing, and mapping on chromosome 7. , 1997, Genome research.

[22]  J. Gilbert,et al.  Genetic studies of autistic disorder and chromosome 7. , 1999, Genomics.

[23]  M. Seike,et al.  The reeler gene-associated antigen on cajal-retzius neurons is a crucial molecule for laminar organization of cortical neurons , 1995, Neuron.

[24]  R C Elston,et al.  Transmission/disequilibrium tests for quantitative traits , 2001, Genetic epidemiology.

[25]  E. Fombonne,et al.  Microcephaly and Macrocephaly in Autism , 1999, Journal of autism and developmental disorders.

[26]  A. Persico,et al.  Adenosine deaminase alleles and autistic disorder: case-control and family-based association studies. , 2000, American journal of medical genetics.

[27]  A. Persico,et al.  Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples. , 2000, American journal of medical genetics.

[28]  G. Meyer,et al.  Embryonic and Early Fetal Development of the Human Neocortex , 2000, The Journal of Neuroscience.

[29]  J. Fleiss.  Statistical methods for rates and proportions , 1974 .

[30]  A. Bailey,et al.  Autism: recent molecular genetic advances. , 2000, Human molecular genetics.

[31]  Cerebellar phenotype of two alleles of the ‘reeler’ mutation on similar backgrounds , 1990, Brain Research.

[32]  D. Curtis,et al.  An extended transmission/disequilibrium test (TDT) for multi‐allele marker loci , 1995, Annals of human genetics.

[33]  C. Francks,et al.  A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. , 1998, Human molecular genetics.

[34]  Yogesh K. Dwivedi,et al.  A decrease of reelin expression as a putative vulnerability factor in schizophrenia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[35]  E. Cook,et al.  Genetics of autism. , 2001, Child and adolescent psychiatric clinics of North America.

[36]  S. Folstein,et al.  An autosomal genomic screen for autism. , 1999, American journal of medical genetics.

[37]  M. Bauman,et al.  Microscopic neuroanatomic abnormalities in autism. , 1991, Pediatrics.

[38]  N. Minshew,et al.  Autism as a disorder of complex information processing , 1998 .

[39]  R Staden.  Computer methods to locate signals in nucleic acid sequences , 1984, Nucleic Acids Res..

[40]  M Knapp,et al.  The transmission/disequilibrium test and parental-genotype reconstruction: the reconstruction-combined transmission/ disequilibrium test. , 1999, American journal of human genetics.

[41]  S Arndt,et al.  Regional brain enlargement in autism: a magnetic resonance imaging study. , 1996, Journal of the American Academy of Child and Adolescent Psychiatry.

[42]  W. Dupont,et al.  Power and sample size calculations. A review and computer program. , 1990, Controlled clinical trials.

[43]  E. Giniger,et al.  Alzheimer's Disease Neurodevelopment Converges with Neurodegeneration , 2000, Cell.

[44]  S. Folstein,et al.  Platelet serotonin, a possible marker for familial autism , 1991, Journal of autism and developmental disorders.

[45]  W. Ewens,et al.  Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). , 1993, American journal of human genetics.

[46]  N. Minshew,et al.  Neuropsychologic functioning in autism: Profile of a complex information processing disorder , 1997, Journal of the International Neuropsychological Society.

[47]  P Bolton,et al.  Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. , 1995, American journal of human genetics.

[48]  K. Mikoshiba,et al.  Distribution of a reeler gene‐related antigen in the developing cerebellum: An immunohistochemical study with an allogeneic antibody CR‐50 on normal and reeler mice , 1996, The Journal of comparative neurology.

[49]  A. Bailey,et al.  A clinicopathological study of autism. , 1998, Brain : a journal of neurology.

[50]  W J Ewens,et al.  The TDT and other family-based tests for linkage disequilibrium and association. , 1996, American journal of human genetics.

[51]  Christopher Gillberg,et al.  Genome-Wide Scan for Autism Susceptibility Genes , 1999 .

[52]  M. Frotscher,et al.  A role for Cajal–Retzius cells and reelin in the development of hippocampal connections , 1997, Nature.

[53]  L. Wing.  The autistic spectrum , 1997, The Lancet.

[54]  T. Terashima,et al.  Expression of reelin, the gene responsible for the reeler mutation, in embryonic development and adulthood in the mouse , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[55]  E. Emamian,et al.  Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice , 1999, Molecular Psychiatry.

[56]  Courtney A. Harper,et al.  A genomic screen of autism: evidence for a multilocus etiology. , 1999, American journal of human genetics.

[57]  Eric Courchesne,et al.  Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism , 1997, Current Opinion in Neurobiology.

[58]  T. Curran,et al.  A protein related to extracellular matrix proteins deleted in the mouse mutant reeler , 1995, Nature.

[59]  George McCloskey,et al.  Leiter International Performance Scale , 1987 .

[60]  Y. Hayashizaki,et al.  The reeler gene encodes a protein with an EGF–like motif expressed by pioneer neurons , 1995, Nature Genetics.

[61]  D. van der Kooy,et al.  The mouse mutation reeler causes increased adhesion within a subpopulation of early postmitotic cortical neurons , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[62]  J. Long,et al.  An E-M algorithm and testing strategy for multiple-locus haplotypes. , 1995, American journal of human genetics.

[63]  A. Goffinet,et al.  Genomic organization of the mouse reelin gene. , 1997, Genomics.