Role of the serotonin transporter gene in the behavioral expression of autism

Abstract

Autism, a pervasive developmental disorder with profound deficits in social relatedness, impairments in language and communication, and symptoms involving repetitive behaviors and restricted interests, is thought to be gene-dependent. 1-3 The well-replicated, but as yet unexplained, platelet hyperserotonemia of autism 4,5 has focused attention on the possible role of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Reports of other 5-HT-related abnormalities in autism 6,7 and the utility of serotonergic agents in partially ameliorating symptoms in some individuals with autism 8 have also served to increase interest in the possible involvement of 5-HT in the etiology and pathophysiology of autism. The important roles of 5-HT in neurodevelopment 9,10 and the rich serotonergic innervation of limbic areas critically involved in social and affiliative behaviors 11 have provided additional, more theoretical, bases for the 5-HT hypothesis.A wide range of 5-HT-related genes can be considered as possible candidate genes in autism. However, the 5-HT transporter gene (HTT, locus SLC6A4), encoding both the neuronal and platelet transporter, 12 is of particular interest for several reasons. Reports of a positive correlation between rates of platelet 5-HT transport and platelet levels of 5-HT 13,14 suggest that the transporter may play a part in the platelet hyperserotonemia of autism. The beneficial effects of agents that block neuronal serotonin transport 8 also focus attention on the possible role of the transporter in the pathophysiology of autism. Additionally, the reported association of a HTT promoter polymorphism with anxiety in the general population, 15 coupled with reports of higher stress responsivity in autism and an increased incidence of anxiety disorder in the families of individuals with autism, 16,17 has further stimulated interest in the HTT in autism. Most intriguing have been discrepant studies reporting preferential transmission of different alleles of the biallelic promoter region polymorphism in individuals with autism. 18,19 The promoter variant consists of a 44 base-pair deletion/insertion in a repeat region of the promoter. The deletion or short (s) allele occurs with a frequency of approximately 43%, while the long (l) form has an allele frequency of 57% in samples of predominately northern European ancestry. 15,20 It is noteworthy that the polymorphism is of apparent functional significance; native lymphoblastoid cell lines with sl or ss genotypes were reported to have approximately onehalf the rates of 5-HT transport, transporter expression, and HTT mRNA levels as those with the ll genotype. 15 After genotyping the HTT promoter alleles in a group of 69 French families with autistic children, the transmission of the alleles was examined to determine their influence on risk or susceptibility to autism. A possible modifying role of the HTT on the behavioral phenotypic expression of autism was also studied. This possibility was examined by comparing allelic transmission across severity sub...

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…234,235 Some studies did not replicate these findings. 214,[236][237][238][239][240][241][242][243] Three studies have assessed the effects of the 5HTTLPR on whole-blood serotonin (5-HT) or platelet 5-HT parameters in AD. 236,237,244 One study 244 did find an increased rate of platelet-5-HT uptake in II genotypes compared to sl and ss.…”

Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder

“…[21][22][23][24] A series of transmission/disequilibrium test (TDT) studies using 5-HTTLPR and VNTR to determine whether SLC6A4 contributes to susceptibility to autistic disorder failed to reveal any consistent evidence of transmission of an allele or haplotype. [25][26][27][28][29][30] Using the TDT, evidence of preferential transmission of the short variant of 5-HTTLPR was found by Cook and colleagues 25 and preferential transmission of the long allele was reported by others. 26,29,30 No evidence of family-based association was reported by Maestrini and colleagues 27 or Persico and colleagues.…”

“…[25][26][27][28][29][30] Using the TDT, evidence of preferential transmission of the short variant of 5-HTTLPR was found by Cook and colleagues 25 and preferential transmission of the long allele was reported by others. 26,29,30 No evidence of family-based association was reported by Maestrini and colleagues 27 or Persico and colleagues. 28 A casecontrolled study has also shown no evidence of association between 5-HTTLPR and autistic disorder.…”

Serotonin transporter gene promoter variants do not explain the hyperserotoninemia in autistic children

“…Family-based association studies between serotonin transporter (5-HTT) gene promoter alleles and autistic disorder have thus far produced contrasting evidence, supporting either linkage/association with the short 'S' allele, 1 or with the long 'L' allele, [2][3][4] or no linkage/association at all. 5,6 Our prior study described a lack of association between 5-HTT gene promoter alleles and autistic disorder in 46 Italian and 44 Caucasian-American complete trios.…”