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.
Persico
A M
AM
Laboratory of Neuroscience, Department of Physiology and Neuroscience, Libera Università Campus Bio-Medico, Via Longoni 83, I-00155 Rome, Italy.
D'Agruma
L
L
Maiorano
N
N
Totaro
A
A
Militerni
R
R
Bravaccio
C
C
Wassink
T H
TH
Schneider
C
C
Melmed
R
R
Trillo
S
S
Montecchi
F
F
Palermo
M
M
Pascucci
T
T
Puglisi-Allegra
S
S
Reichelt
K L
KL
Conciatori
M
M
Marino
R
R
Quattrocchi
C C
CC
Baldi
A
A
Zelante
L
L
Gasparini
P
P
Keller
F
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001321:Autistic Disorder / Q000453:epidemiology* / Q000235:genetics*; D001923:Brain Chemistry / Q000235:genetics; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D005091:Exons; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites / Q000235:genetics; D000091042:Reelin Protein; D012307:Risk Factors; D012697:Serine Endopeptidases; D012701:Serotonin / Q000502:physiology; D012886:Skull / Q000033:anatomy & histology; D018911:Trinucleotide Repeats
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D022821:RNA Splice Sites; D000091042:Reelin Protein; D012701:Serotonin; C000717127:RELN protein, human; D012697:Serine Endopeptidases