Deregulation of EIF4E: a novel mechanism for autism.

BACKGROUND: Autism is a common childhood onset neurodevelopmental disorder, characterised by severe and sustained impairment of social interaction and social communication, as well as a notably restricted repertoire of activities and interests. Its aetiology is multifactorial with a strong genetic basis. EIF4E is the rate limiting component of eukaryotic translation initiation, and plays a key role in learning and memory through its control of translation within the synapse. EIF4E mediated translation is the final common process modulated by the mammalian target of rapamycin (mTOR), PTEN and fragile X mental retardation protein (FMRP) pathways, which are implicated in autism. Linkage of autism to the EIF4E region on chromosome 4q has been found in genome wide linkage studies. METHODS AND RESULTS: The authors present evidence that directly implicates EIF4E in autism. In a boy with classic autism, the authors observed a de novo chromosome translocation between 4q and 5q and mapped the breakpoint site to within a proposed alternative transcript of EIF4E. They then screened 120 autism families for mutations and found two unrelated families where in each case both autistic siblings and one of the parents harboured the same single nucleotide insertion at position -25 in the basal element of the EIF4E promoter. Electrophoretic mobility shift assays and reporter gene studies show that this mutation enhances binding of a nuclear factor and EIF4E promoter activity. CONCLUSIONS: These observations implicate EIF4E, and more specifically control of EIF4E activity, directly in autism. The findings raise the exciting possibility that pharmacological manipulation of EIF4E may provide therapeutic benefit for those with autism caused by disturbance of the converging pathways controlling EIF4E activity.

BDNF gene is a risk factor for schizophrenia in a Scottish population.

Schizophrenia is a severe psychiatric disease with a strong genetic component. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar (BP) disorders. The present study has examined two polymorphisms in linkage disequilibrium in the BDNF gene, which have been variously reported as associated with schizophrenia and BP. In our study, 321 probands with a primary diagnosis of schizophrenia or schizoaffective disorder, and 263 with a diagnosis of bipolar affective disorder, were examined together with 350 controls drawn from the same geographical region of Scotland. The val66met single-nucleotide polymorphism (SNP) showed significant (P = 0.005) association for valine (allele G) with schizophrenia but not bipolar disorder. Haplotype analysis of val/met SNP and a dinucleotide repeat polymorphism in the putative promoter region revealed highly significant (P < 1 x 10(-8)) under-representation of the methionine or met-1 haplotype in the schizophrenic but not the BP population. We conclude that, although the val66met polymorphism has been reported to alter gene function, the risk may depend upon the haplotypic background on which the val/met variant is carried.

Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder.

There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.

Dopamine system genes not linked to social phobia.

Social phobia, particularly in its generalized form, has a genetic component in its etiology as suggested by positive twin studies and child temperament studies of social anxiety. Observations from functional imaging research suggest that dopamine function may be abnormal in the brains of patients with social phobia. Our investigation examined polymorphisms in the dopamine D2, D3 and D4 receptor genes, plus the dopamine transporter gene in a sample consisting of 17 multiplex social phobia families. We employed both parametric and non-parametric methods to test for linkage. Linkage was excluded for all loci under the broad diagnostic category. In the medium diagnostic category, the D3 receptor gene showed non-significant positive LOD scores (LOD = 0.62). We are able to clearly exclude a major effect for each of the four dopamine gene markers under the broad diagnosis of social phobia. Additional studies of dopamine system genes will be necessary to define clearly their role in social phobia.

An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: a common expansion locus.

Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with schizophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with control individuals have previously been reported, implying a possible etiological role for trinucleotide repeats in these diseases. Two unstable CAG/CTG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indicate that the majority of individuals with large repeats as detected by repeat-expansion detection (RED) have large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. Using RED, we have identified a BPAD individual with a very large CAG/CTG repeat that is not due to expansion at SEF2-1B or ERDA1. From this individual's DNA, we have cloned a highly polymorphic trinucleotide repeat consisting of (CTA)n (CTG)n, which is very long ( approximately 1,800 bp) in this patient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fragile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.6%) of 231 meioses. Large alleles (>100 repeats) were observed in 14 (1. 25%) of 1,120 patients with psychosis, borderline personality disorder, or juvenile-onset depression and in 5 (.7%) of 710 healthy controls. Very large alleles were also detected for Centre d'Etude Polymorphisme Humaine (CEPH) reference family 1334. This triplet expansion has recently been reported to be the cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affected by SCA or with known family history of SCA. The high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. Thus, it seems unlikely that expansion alone causes SCA8; other genetic mechanisms may be necessary to explain SCA8 etiology.

No evidence for linkage of the CHRNA7 gene region in Canadian schizophrenia families.

Schizophrenia patients demonstrate a deficiency in the filtering of sensory information, and one specific measure involves a response to the second of a pair of auditory stimuli. A neurophysiological measure of this consists of the electroencephalographic response to pairs of auditory signals, emitted fractions of a second apart. Schizophrenic patients and some of their unaffected relatives show a failure of inhibition of a second tone if it occurs 50 msec after the first. A recent genome scan indicated that the gating defect is linked to the alpha 7 neuronal nicotinic acetyl choline receptor gene on chromosome 15. We genotyped 5 schizophrenia families with a total of 96 subjects with a dinucleotide polymorphic marker located less than 120 kb from the first exon of the alpha 7 neuronal nicotinic acetylcholine receptor gene. Linkage analysis was undertaken using parametric and nonparametric statistical methods. The results of the parametric analysis showed negative lod scores under both narrow and broad diagnosis (lod = -3.6 and -4.8, respectively, at theta = 0), and dominant and recessive modes of transmission of the disease. Nonparametric analysis using GENEHUNTER produced nonsignificant NPL scores (NPL = -0.4 and -0.3 for broad and narrow diagnoses, respectively). In summary, we did not find any evidence that the alpha 7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is linked to schizophrenia. However, we have not been able to assess the P50 measures in these families.