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Genetic and expression analyses reveal elevated expression of syntaxin 1a ( stx1a) in high functioning autism

International Journal of Neuropsychopharmacology, Page 1 of 12. Copyright f 2008 CINP Genetic and expression analyses reveal elevated expression of syntaxin 1A (STX1A) in highfunctioning autism Kazuhiko Nakamura1*, Ayyappan Anitha1*, Kazuo Yamada2*, Masatsugu Tsujii3,4,Yoshimi Iwayama2, Eiji Hattori2, Tomoko Toyota2, Shiro Suda1, Noriyoshi Takei1,Yasuhide Iwata1, Katsuaki Suzuki1, Hideo Matsuzaki5, Masayoshi Kawai1,Yoshimoto Sekine1, Kenji J. Tsuchiya1, Gen-ichi Sugihara4, Yasuomi Ouchi4,6,Toshiro Sugiyama7, Takeo Yoshikawa2 and Norio Mori1,4 1 Department of Psychiatry and Neurology, Hamamatsu University School of Medicine,Hamamatsu, Japan2 Laboratory of Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan3 Faculty of Sociology, Chukyo University, Toyota, Aichi, Japan4 The Osaka-Hamamatsu Joint Research, Center for Child Mental Development, Hamamatsu University School of Medicine,Hamamatsu, Japan5 The Osaka-Hamamatsu Joint Research, Center for Child Mental Development, Graduate School of Medicine,Osaka University, Japan6 The Positron Medical Center, Hamamatsu Medical Center, Hamamatsu, Japan7 Aichi Children’s Health and Medical Center, Obu, Aichi, Japan Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities ofserotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), whichmodulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTTexpression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynapticprotein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio associationstudy using DNA samples from 249 AGRE trios with autistic probands. Only male probands were selec-ted, since autism is more prevalent among males. The probands of 102 trios had IQ>70, and were con-sidered as high functioning autism (HFA). In transmission disequilibrium test (TDT) analysis, rs2293485(p=0.034) and rs4717806 (p=0.033) showed nominal associations with HFA ; modest haplotype associ-ation was also observed. The SNPs that showed associations were related to early developmental abnor-malities (ADI-R_D). We further compared STX1A mRNA expression in the lymphocytes of drug-naiveHFA patients (n=12) and age- and sex-matched controls (n=13). STX1A expression in the HFA groupwas significantly higher (p=0.001) than that of controls. Thus, we suggest a possible role of STX1A in thepathogenesis of HFA. During early childhood, there is a period of high brain serotonin synthesis that isdisrupted in autistic children ; STX1A might influence the serotonergic system during this stage of neuro-development, as implied by the association with ADI-R_D.
Received 27 September 2007 ; Reviewed 20 November 2007 ; Revised 9 May 2008 ; Accepted 14 May 2008 Key words : AGRE, high functioning autism, lymphocyte mRNA, serotonin transporter, syntaxin 1A.
communication deficits in combination with restrictedand repetitive behaviours and interests (Kanner, 1943).
Autism is a pervasive developmental disorder diag- Based on converging evidence from diverse studies, nosed in early childhood, characterized by social and the serotonin (5-HT) system can be considered asa logical candidate in autism pathology. The 5-HT Address for correspondence : K. Nakamura, M.D., Ph.D., Department system has been found to be developmentally dys- of Psychiatry and Neurology, Hamamatsu University School of regulated in autism (Anderson, 1994). 5-HT acts as a Medicine, Hamamatsu, 431-3192, Japan.
trophic and differentiation factor (Lavdas et al., 1997), Tel. : +81-53-435-2295 Fax : +81-53-435-3621 in addition to its role as a neurotransmitter. Hyper- E-mail : nakamura@hama-med.ac.jp* These authors contributed equally to this work.
serotonaemia has been observed in the platelets of subjects with autism (Ciaranello, 1982 ; Hanley et al., lymphocytes (PBL) of drug-naive autistic patients and control subjects, since lymphocytes are considered Several studies have reported the association of as a convenient and accessible alternative to brain serotonin transporter (5-HTT) polymorphisms with samples for biochemical and genetic investigations autism (Betancur et al., 2002 ; Cook et al., 1997 ; Klauck of the functions of central nervous system (CNS) et al., 1997 ; Tordjman et al., 2001 ; Yirmiya et al., 2001).
(Gladkevich et al., 2004). We also examined the re- 5-HTT effects the recycling of 5-HT by mediating its lationship between mRNA expression and genotypes presynaptic reuptake on termination of serotonergic neurotransmission ; it is also the major target of selectiveserotonin reuptake inhibitors (SSRIs) (Moore et al.,2004), which have been proven to be efficient in re- ducing compulsive and stereotyped behaviours and hyperactivity in autism patients (McDougle et al.,1996). 5-HTT (SLC6A4) is located in 17q11.2, which has been implicated as an autism linkage region ; This study was approved by the Ethics Committee of however, other studies have reported different results Hamamatsu University School of Medicine. We ob- with stronger linkage findings (Freitag, 2007). 5-HTT tained DNA samples from trio families recruited to the gene promoter variants have been suggested to exert a Autism Genetic Resource Exchange [AGRE (http:// detectable, albeit small effect on 5-HT blood levels in www.agre.org) ; Geschwind et al., 2001] ; 249 trio autistic individuals (Lesch et al., 1996) ; however, as families with a male proband diagnosed for autism suggested by Persico et al. (2002) enhanced 5-HT according to Autism Diagnostic Interview – Revised blood levels in autism patients, but not in first-degree (ADI-R ; Lord et al., 1994) and Autism Diagnostic Ob- relatives with the promoter variant, indicate inter- servation Schedule (ADOS ; Lord et al., 1989), were active contributions to hyperserotonaemia both by 5- selected. Out of the 249 trios, 235 trios were derived HTT variants and by other autism-related loci. Thus, from multiplex families ; only male probands [age factors that regulate the cell surface expression of 5- 9.65¡4.87 yr (mean¡S.D.)] were selected, since autism HTT might also have a crucial role in the regulation of has a strong gender bias with a 4 : 1 (male : female) serotonergic neurotransmission, and therefore, in the gender ratio. Additional selection criteria required that (i) there be no possible non-idiopathic autism flag One candidate 5-HTT-regulatory protein is the pre- and (ii) all the trios be Caucasian. ADI-R data was synaptic protein, syntaxin 1A (STX1A) ; this 35-kDa available for all the 249 affected individuals ; however, membrane protein belonging to the syntaxin fam- ADOS testing was available for only 163, and intelli- ily (Bennett et al., 1992, 1993 ; Inoue et al., 1992) was gence quotient (IQ) testing for only 112 out of the 249 originally identified as a neuron-specific antigen autistic individuals. The autistic probands of 102 trios (Barnstable et al., 1985). Together with the synapto- had IQ>70, and were considered as the high func- some-associated protein 25 kDa (SNAP-25) and the vesicle-associated membrane protein (VAMP), STX1A We had taken care to exclude the commonly known forms the soluble N-ethylmaleimide-sensitive factor genetic causes of autism (e.g. fragile X syndrome), and attachment protein receptor (SNARE) complex, which other neurological disorders such as tuberous sclerosis is vital for chemical neurotransmission (Rothman, In-vitro studies have shown that STX1A interacts with 5-HTT, regulating the subcellular localization andexpression of 5-HTT (Haase et al., 2001 ; Quick, 2002).
The genomic structure of STX1A is based on the UCSC STX1A gene is located at 7q11.23 ; recently, speech de- May 2004 draft assembly of human genome (http:// lay and autism spectrum behaviours have been found www.genome.ucsc.edu). STX1A consists of 10 exons to be associated with duplication of 7q11.23 (Berg et al., spanning a genomic stretch of 20.42 kb (mRNA 2064 bases) (Figure 1). In 20 unrelated autism samples selec- In this trio association study, we examined the SNP ted randomly from among the AGRE probands, all the and haplotype associations of STX1A with autism ; we exons, splice boundaries, and 5k- and 3k-flanking re- also examined the association of STX1A SNPs with gions of the gene were screened for polymorphisms by ADI-R phenotypic data. Further, we compared the direct sequencing of the respective PCR products.
expression of STX1A mRNA in the peripheral blood Primer sets used for PCR amplification are listed in Figure 1. Genomic structure of STX1A and locations of SNPs. Exons are indicated by boxes, with translated regions in closedboxes, and untranslated regions in open boxes ; SNP positions are denoted by arrows.
Table 1. PCR was performed with an initial denatura- Hardy–Weinberg Equilibrium (HWE) using the tion at 95 xC for 12 min, followed by 35 cycles at 94 xC Haploview software version 3.2 (http://www.broad.
for 30 s, 55–60 xC (optimized for each primer pair) mit.edu/mpg/haploview). Markers were tested for for 30 s, 72 xC for 1 min, and a final extension at 72 xC association by transmission disequilibrium test (TDT), for 7 min, using AmpliTaq Gold DNA polymerase (Ap- using the TDTPHASE program of the UNPHASED plied Biosystems, Foster City, CA, USA). Direct se- software package version 2.403 (http://portal.litbio.
quencing of PCR products was done using the BigDye org) ; expectation maximization (EM) algorithm was Terminator Cycle Sequencing kit v3.1 (Applied used to resolve uncertain haplotypes, to infer missing Biosystems) in ABI PRISM 3100 Genetic Analyzer genotypes and to provide maximum-likelihood esti- Additional SNPs were selected using the infor- One-way analysis of variance [ANOVA ; GraphPad mation from International HapMap Project (http:// Prism, version 4.00 (GraphPad Software, San Diego, www.hapmap.org) and National Centre for Biotech- CA, USA)] was used to examine the variability in the nology Information (NCBI dbSNP : http://www.ncbi.
distribution of ADI-R phenotypic data [ADI-R_A (so- nlm.nih.gov/SNP). On the basis of their genomic cial interaction), ADI-R_BV (verbal communication), locations and minor allele frequencies (MAF >0.1) ADI-R_C (restricted, repetitive and stereotyped pat- in the Caucasian population, 10 SNPs were chosen terns of behaviour), ADI-R_D (developmental abnor- for our analysis, to span the STX1A gene as evenly as mality prior to 36 months)] across the homozygous possible. The SNPs used in the study, and their loca- and heterozygous genotypes of SNPs that showed as- Linkage disequilibrium (LD) plot was constructed using the r2 correlation coefficient (Devlin and Risch, 1995) pair-wise LD values between markers were es- Assay-on-demand/Assay-by-design SNP genotyping timated using Haploview software. Subsequently, products (Applied Biosystems) were used to score associations of haplotypes (frequency >0.01) belong- SNPs, based on the TaqMan assay method (Ranade ing to the various haploblocks of STX1A were also et al., 2001). Genotypes were determined using the ABI 7900 Sequence Detection System (SDS ; AppliedBiosystems), and analysed using SDS version 2.0 soft- We obtained blood samples from 12 drug-naive autistic patients (age 21.4¡2.31 yr) and 13 age- PedCheck program version 1.1 (http://www.watson.
matched (22.3¡1.93 yr) healthy controls. All the hgen.pitt.edu) was used to identify and eliminate all patients and controls were males, and of Japanese Mendelian inheritance inconsistencies in the trio origin ; written informed consent was obtained from genotype data. All the SNPs were tested for Table 1. PCR primers used for the mutation screening of STX1A gene The autistic patients were diagnosed according to sion), respectively. Obsessional/repetitive behaviours ADI-R (Lord et al., 1994), by trained and certified psy- were clinically rated using the Yale–Brown Ob- chiatrists (K.J.T., A.S.). All patients met the autism cri- sessive–Compulsive Scale (YBOCS ; Goodman et al., teria of DSM-IV (APA, 1994) and ICD-10 (WHO, 1992).
1989a, b, Japanese version). Additional aggression The patients underwent screening, and were excluded symptoms were also assessed using the aggression if they had any major medical or psychiatric conditions.
questionnaire (AQ ; Buss and Perry, 1992, translation We had taken care to exclude the commonly known in Japanese). A faux pas detection task was used to genetic causes of autism (e.g. fragile X syndrome), and measure theory of mind (Baron-Cohen et al., 1999, other neurological disorders such as tuberous sclerosis Stone et al., 2003, translation in Japanese). All the and neurofibromatosis. All the patients were of the evaluations were conducted by a trained research HFA type ; the average IQ scores were measured by the Wechsler Adult Intelligence Scale – Revised (WAIS-R ; All the controls were free of medications, and under- went screening to exclude neurological, developmen- We used the following instruments for the assess- tal, or psychiatric disorders and mental retardation ; ment of autistic symptoms. Comorbid anxiety and none of them met any of the relevant criteria of depressive symptoms were assessed using the DSM-IV. The average IQ of the control subjects (meas- Hamilton Anxiety Rating Scale (HAMA ; Hamilton, ured by WAIS-R, Wechsler, 1981, Japanese version) 1959, Japanese version) and the Hamilton Depression did not differ significantly from that of the HFA pa- Rating Scale (HAMD ; Hamilton, 1960, Japanese ver- Table 2. Single SNP transmission disequilibrium test (TDT) results of STX1A SNPs HFA, High functioning autism ; T, transmitted ; UTR, untranslated region.
a Common allele is listed first.
b Based on the parental genotypes of 249 trios.
c T % of common allele is listed.
d Computed on the basis of likelihood ratio test ; significant p values (<0.05) are indicated in bold italics.
e 10 000 permutations.
(GAPDH) that served as the endogenous reference,were purchased from Applied Biosystems (Assay-on- Peripheral blood (20 ml) was drawn from the cubital DemandTM gene expression products Hs00195648 and vein into EDTA-containing plastic syringes. Lym- Hs99999905, respectively). All reactions were per- phocytes were isolated from blood samples by the formed in duplicate, according to the manufacturer’s Ficoll-Paque gradient method, and total RNA was protocol. A comparative threshold cycle (C extracted using RNAzolB reagent (Sawady, Tokyo, validation experiment was performed to check if the Japan) according to the manufacturer’s instructions.
efficiencies of target and reference amplifications were RNA samples were quantified by analysing the approximately equal (the slope of the log input amount absorbance at 260 nm in a UV spectrophotometer.
Complementary DNA (cDNA) was synthesized by T<0.1). One sample was randomly chosen as the calibrator and was amplified in each plate to correct for first-strand reverse transcriptase (RT) reaction using the experimental differences among consecutive PCR Random Primer and M-MLV reverse transcriptase runs. The amounts of STX1A mRNA were normalized to the endogenous reference and expressed relative We had maintained similar conditions during the to the calibrator as 2xDDCT (comparative C collection and processing of all the samples since cir- cadian regulation of STX1A has been reported(Allaman-Pillet et al., 2004). The blood samples were collected at around 10:00 hours on the days assignedfor sample collection. Lymphocyte isolation and RNA Statistical calculations were performed using SPSS extraction were done immediately thereafter, under statistical package, version 11.0.1 (SPSS Co. Ltd, Tokyo, Japan) and GraphPad Prism. The differencein STX1A expression between groups was analysedusing t test. Correlation between the various clinical Quantitative reverse transcriptase polymerase chain features of HFA group and STX1A expression was examined by Spearman’s rank correlation test. Fur- Real-time qRT–PCR analysis was performed using ther, regression analysis was carried out to check ABI PRISM 7900 Sequence Detection System (Ap- the effect of comorbidities, including obsession- plied Biosystems). TaqMan primer/probes for STX1A compulsion (YBOCS scores) and aggression, on and for glyceraldehyde-3-phosphate dehydrogenase Figure 2. Comparison of the distribution of ADI-R_D scores across the homozygous and heterozygous genotypes of(a) SNP08 (p=0.036), (b) SNP03 (p=0.04), (c) SNP09 (p=0.036), (d) SNP10 (p=0.029), in the probands of high functioningautism (HFA) trios.
Relationship between mRNA expression and genotypes results are shown in Table 2. In the TDT of HFA trios,SNP04 (p=0.034, OR 1.54, 95 % CI 1.03–2.29) and All the samples from the mRNA expression study SNP08 (p=0.033, OR 0.63, 95 % CI 0.41–0.96) showed were genotyped for the SNPs that showed associations nominal associations. Overtransmission was observed in the trio association study. Using the Kruskal–Wallis for the minor allele T (56.07 %) of SNP04 (rs941298 ; test, we examined the relationship between genotypes exon 3, D68D) and for the minor allele A (57.69 %) of SNP08 (rs4717806). SNP03 (p=0.054), SNP05 (p=0.053), SNP09 (p=0.050) and SNP10 (p=0.050) showed tendencies for association with HFA. The global p value, however, was not significant (p=0.124).
None of the SNPs showed significant association in No new mutations were observed in the coding orregulatory regions of the gene, other than the SNPs We examined the associations of ADI-R phenotypicdata (ADI-R_A, ADI-R_BV, ADI-R_C, and ADI-R_D) with the SNPs that showed nominal associations in Mendelian inheritance inconsistencies were not ob- single SNP TDT. In the HFA trios, significant associ- served for any of the SNPs. More than 98 % of the ation with ADI-R_D scores was observed for SNP08 genotypes were scored for each SNP ; none of the SNPs (p=0.036) ; ADI-R_D was lower in the A/A group of this SNP (Figure 2a). We also examined the associ- TDT was performed separately for the whole set of ations of SNPs that showed tendency for association in 249 trios and for the HFA subgroup of 102 trios ; the single SNP TDT. SNP03 (p=0.040), SNP09 (p=0.036) correlation was observed between any of the clinical features of HFA group and STX1A expression (Table 4). Further, regression analysis showed that there is no effect of YBOCS/aggression on STX1A By Kruskal–Wallis test, the relationship between geno- types and STX1A mRNA expression was examined for SNP04 and SNP08, which showed nominal asso- Figure 3. Haplotype block structure of STX1A based on r2 ciations with HFA in TDT analysis. SNP08 showed a values calculated from 102 high functioning autism (HFA) tendency for gene dose effect, with the following trend : expression of A/A genotype (mean¡S.D.)(0.243¡0.162)<expression of A/T genotype (0.293¡0.143)<expression of T/T genotype (0.462¡0.023) ; and SNP10 (p=0.029) showed significant associations however, the difference was not statistically signifi- with ADI-R_D ; the scores were lower in the A/A group of SNP03, in the C/C group of SNP09 and in theC/C group of SNP10 (Figure 2b–d, respectively).
After adjusting for IQ effects with univariate ana- lysis of variance, there were only tendencies for In this study, STX1A mRNA expression was signifi- association with ADI-R_D (SNP08, p=0.070 ; SNP03, cantly higher in the lymphocytes of drug-naive HFA p=0.070 ; SNP09, p=0.070 ; SNP10, p=0.055).
patients compared with controls. Lymphocytes are No associations were observed with other pheno- considered as excellent neural probes for studying typic data. In the whole group of 249 trios, there were neuropsychiatric disorders due to (i) altered lympho- no significant associations with any of the ADI-R cyte functions in neuropsychiatric conditions, (ii) ex- pression of neuroactive proteins and processes inlymphocytes, and (iii) similarities of hormonal effects on the nervous system processes and lymphocyte LD analysis identified a single haploblock across the physiology (reviewed by Gladkevich et al., 2004). In STX1A gene, comprising SNP03 to SNP10 (Figure 3).
the present study, there was no significant correlation The LD pattern observed in our study is similar to that between STX1A expression and any of the clinical reported for the 30 CEU (CEPH) trios in the HapMap features of the HFA group ; therefore, altered STX1A expression may be implicated in the general patho-physiology of HFA, rather than in the symptoms of the disease. The possibilities of using the enhanced ex-pression of STX1A as a peripheral marker in the di- The results of haplotype association analysis are agnosis of HFA may be explored. However, our study shown in Table 3. The haplotype ATACCTCC showed is limited by small sample size ; therefore, replication a nominal association in the HFA subgroup of 102 in a larger sample size is warranted.
trios (p=0.044) ; however, this was not significant after Lymphoblastoid cells lines have been reported as the permutation test (10 000 permutations). None of viable tools for identifying the genes associated with the haplotypes showed any significant association in autism (Baron et al., 2006 ; Hu et al., 2006 ; Nishimura et al., 2007). There is a close association between thestate of the immune system, particularly lymphocytes, and major psychiatric disorders including autism Descriptive clinical data of the autism samples is pro- (Ashwood et al., 2006 ; Krause et al., 2002). STX1A is a vided in Table 4. STX1A expression in the drug-naive neuron-specific antigen (Barnstable et al., 1985), HFA group (0.38¡0.39) was found to be significantly which, in association with SNAP-25 and VAMP, forms higher (t=x4.37, d.f.=14, p=0.001) than that of the the SNARE complex that is vital for chemical neuro- control group (0.17¡0.06) (Figure 4). No significant transmission (Rothman, 1994 ; Sollner et al., 1993). In a Table 3. Haplotype associations of SNPs belonging to the single LD block of STX1A in102 HFA trios LD, Linkage disequilibrium ; HFA, high functioning autism.
a All possible combinations of haplotypes with frequency >0.01.
b Significant p values (<0.05) are indicated in bold italics.
c 10 000 permutations.
Table 4. Descriptive data on autism samples and their correlation with STX1A mRNAexpression HAMD, Hamilton Depression Rating Scale ; HAMA, Hamilton Anxiety Rating Scale ;YBOCS, Yale–Brown Obsessive–Compulsive Scale.
process similar to the exocytosis of neurotransmitters, comparable to the STX1A expression during their first STX1A and other SNARE proteins are involved in a years of life, which is the most critical period for the process of exocytosis of lytic granules, mediating tar- formation of neural wiring patterns.
get cell death in the PBLs that play a pivotal role in the In the trio association study, nominal SNP and body’s defence against infection (Hong, 2005). The haplotype associations were observed with HFA.
presence of sympathetic fibres in lymphoid tissues None of the SNP and haplotype associations will re- suggests a direct contact area for neural signalling main significant after multiple testing correction ; cascade with the immune cells (Felten et al., 1987).
however, it is difficult to apply a Bonferroni correction Thus, lymphocyte STX1A expression might be indi- in this study, since strong LD was observed between cative of CNS expression. In animal models, STX1A SNP03 and SNP10. Further, single genes are likely to expression has been shown to be more or less constant have only small individual effects in complex dis- after the embryonic and immediate postnatal stages orders like autism. Among the two SNPs that showed (Biranowska et al., 2002 ; Shimohama et al., 1998).
nominal associations with HFA, rs2293485 is a syn- Therefore, the expression pattern of STX1A in our onymous exonic SNP, while rs4717806 is an intronic study subjects with an average age of 22 yr might be SNP. The other SNPs that showed tendencies for should precede the appearance of clinical symptoms.
The importance of 5-HT in several aspects of prenataland postnatal brain development that are related to autism is well documented. Humans undergo a periodof high brain 5-HT synthesis capacity during early childhood, which is disrupted in autistic children (Chugani et al., 1999). Thus, STX1A might be involvedin the pathogenesis of autism by influencing the sero- tonergic system, during the early stages of brain de- velopment. However, after adjustment for IQ, there were only tendencies for association with ADI-R_D.
There was no relation with other ADI-R subscores (ADI-R_A, ADI-R_BV, ADI-R_C), which reflect the During the postnatal stages of neurodevelopment, the expression of 5-HTT might be a prerequisite for the neurodevelopmental functions exerted by 5-HT. In- Figure 4. t test comparison of STX1A mRNA levels in the vitro studies have shown that 5-HTT expression is lymphocytes from control subjects and drug-naive high regulated by STX1A (Haase et al., 2001 ; Quick, 2002).
functioning autism (HFA) patients. Expression level of In cultured cells, STX1A has been found to interact STX1A is normalized against that of glyceraldehyde-3- with 5-HTT, modulating the cell-surface expression of phosphate dehydrogenase (GAPDH). Horizontal bars 5-HTT (Haase et al., 2001). Cells transfected with indicate means. A significant difference in STX1A expression STX1A cDNA showed a decrease in the number of 5- was observed between the two groups (p=0.001).
HTT molecules expressed on the cell surface ; the de-crease in 5-HTT expression was suggested to be association are also intronic SNPs. Therefore, the as- caused either by an inhibition of the recycling of pre- sociated SNPs may not have a direct influence on viously internalized 5-HTT or by a blocking of the STX1A expression. It is possible that the expression is trafficking of newly synthesized 5-HTT to the plasma regulated by additional trans-acting factors in a net- membrane. Studies using thalamocortical neuronal cultures also have shown that STX1A affects the loca- Considering sample homogeneity, we had selected lization and cell-surface expression of 5-HTT (Quick, predominantly high-functioning trio samples, where 2002). Thus, STX1A might be suggested to influence all the subjects were strictly diagnosed with autistic the serotonergic system by modulating the expression disorder. Since mental retardation consists of various aetiologies, HFA samples can be considered to be An alternate mode of action of STX1A may be relatively free from non-specific environmental or through its interaction with the glutamatergic system genetic risks for their impairments. We had used all (Fan et al., 2006 ; Yu et al., 2006). Glutamate, the major available AGRE cases that satisfied our strict selection excitatory neurotransmitter in the brain, plays a vital criteria at the time of subject selection.
role in brain development, affecting neuronal mi- We observed an association of ADI-R_D scores with gration, neuronal differentiation, axon genesis, and the SNPs that showed nominal associations or ten- neuronal survival (Coyle et al., 2002). STX1A promotes dencies for association with HFA. This observation in the endocytic sorting of the glutamate transporter HFA patients who had been diagnosed for autism is EAAC1, leading to inhibition of glutamate transport interesting, since ADI-R_D reflects developmental ab- (Yu et al., 2006). Several studies have implicated ab- normalities observed in autism prior to 36 months ; normalities of glutamatergic neurotransmission in the delayed speech, unusual socio-emotional reactions pathophysiology of autism (reviewed by McDougle et and poor attentions to and exploration of the en- al., 2005). Glutamate-related genes have also been vironment, are among the first clinically noticeable shown to be important in the pathology of autism behavioural symptoms of autism during the second and third years of life (Dahlgren and Gillberg, 1989 ; In conclusion, we suggest a possible role of STX1A De Giacomo and Fombonne, 1998). Since autism is in the pathogenesis of HFA ; this is the first report of an a pervasive developmental disorder, neuroanatomi- association between STX1A and HFA. In autism, cal, neurochemical and neurobiological abnormalities mental retardation implies the involvement of more risk factors and genes ; this might be the reason that Bennett MK, Calakos N, Scheller RH (1992). Syntaxin : a the autism group, as a whole, was not associated with synaptic protein implicated in docking of synaptic vesicles STX1A. The association of STX1A with the HFA group at presynaptic active zones. Science 257, 255–259.
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Betancur C, Corbex M, Spielewoy C, Philippe A, Laplanche We gratefully acknowledge the support of the Autism JL, Launay JM, Gillberg C, Mouren-Simeoni MC, Hamon Genetics Resource Exchange (AGRE, www.agre.org).
M, Giros B, Nosten-Bertrand M, Leboyer M (2002).
Serotonin transporter gene polymorphisms and This work was supported by Research on Brain hyperserotonemia in autistic disorder. Molecular Psychiatry Science Funds from the Ministry of Health Labor and Welfare, Japan and a Grant-in-Aid for Scientific Re- Biranowska J, Dziewiatkowski J, Ludkiewicz B, Morys J search (C) from the Ministry of Education, Culture, (2002). Developmental changes of synaptic proteins Sports, Science and Technology of Japan. We thank expression within the hippocampal formation of the rat.
Hosoya Teruyo for technical assistance.
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