Evaluation of GABA(A) Receptor (GABAA-R) Subunits Polymorphisms in An Argentinean Population of Autism Spectrum Disorders (ASD)

Thursday, May 17, 2012
Sheraton Hall (Sheraton Centre Toronto)
10:00 AM
C. V. Sesarini1, A. R. Cajal2, L. Costa1, M. Naymark3, M. García Coto4, R. C. Pallia3, G. E. Agosta3, N. Grañana5 and P. F. Argibay1, (1)Brain and Cognition Laboratory, Instituto de Ciencias Básicas y Medicina Experimental (ICBME), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina, (2)Instituto de Ciencias Básicas y Medicina Experimental (ICBME), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina, (3)Hospital Italiano de Buenos Aires, Buenos Aires, Argentina, (4)Centro de Investigaciones del Desarrollo Psiconeurológico (CIDEP), Buenos Aires, Argentina, (5)Hospital Carlos G Durand, Buenos Aires, Argentina
Background: Some forms of ASD may be associated with disproportionate high level of excitation (weak inhibition) in neural circuits. More excitable cortex is more poorly functionally differentiated and would lead to broad-ranging abnormalities in cognition and motor control. Moreover, ‘noisy’ (hyperexcitable) cortex is inherently unstable and susceptible to epilepsy.

ASDs can be conceptualized as a genetic dysfunction that disrupts development and function of brain circuits mediating social cognition and language. Disconnection between different cerebral modulus, as result of congenital disturbance of cerebral development, could lead to altered information processing. The neocortical architecture is organized in minicolumns of functionally-related glutamatergic and GABAergic neurons processing together thalamic input. GABAergic neurons participate in controlling functional integrity and segregation in minicolumns providing lateral inhibition of activity coming from bordering ones. Polymorphisms in GABAA-R subunits have been associated with epilepsy. Indeed, GABAergic abnormalities have been involved in ASD.

Objectives: To evaluate polymorphisms in GABAA-R subunits genes in Argentine ASD patients versus healthy controls.

Methods: 136 ASD (DSM-IV) and 104 controls were included. Eighteen SNPs were genotyped in GABAA-R subunits: α1 (GABRA1), β3 (GABRB3), δ (GABRD), γ2 (GABRG2) through PCR-RFLP and DNA-sequencing. Allele and genotype frequencies, HWE and LD were analysed using UNPHASED 3.1 and SNPStats; and chromatograms using DNASTAR Lasergene. Restriction enzymes’ (VspI-rs4906902, BstUI-rs20317, NcoI-lis-289-met) products were visualized on 3% agarose gel.

Results: Eleven polymorphisms studied (GABRA1: ala-322-asp; GABRB3: rs57294806; GABRD: glu-177-ala, rs6688232, rs3795278, rs3795279, arg-220-his, rs34122464, rs75981360; and GABRG2: lis-289-met, rs17855004) were not observed in controls or ASD patients.

No significant differences in allele and genotype frequencies (p>0.05) were observed between patients and controls for SNPs in GABRB3: rs3212337, rs3212338, rs4906902, rs20317; GABRD: rs41307846, novel rs140480490: -/C; and GABRG2: rs211037; both populations in HWE (p>0.05). SNPs in GABRB3 were in LD (p<0.05), but not polymorphisms in GABRD (p>0.05). Worth noting, rs41307846-GABRD and rs211037-GABRG2 were in LD (p=0.0187). Remaining combinations were not in LD (p>0.05). No significant difference between cases and control was found in the haplotype study. Although to mention, haplotypes AA- (rs3212337, rs4906902, no-C insertion: rs140480490), ATA- (rs3212337, rs3212338, rs4906902, no-C insertion rs140480490) and AAC- (rs3212337, rs4906902, rs20317, no-C insertion rs140480490) showed marginal significant association with ASD (p<0.075).

No significant difference between sexes was observed (p> 0.05).

Conclusions: Eleven SNP analysed, and described elsewhere, in GABRA1, GABRB3, GABRD and GABRG2 were not present in our Argentinean population (neither patients nor controls), not contributing to the ASD phenotype. Although the rest of the polymorphisms studied did not show significant association with ASD individuals, haplotype results in GABRB3 and GABRD should be taken into consideration for further studies. Clinical data from patients (clinical and cognitive symptoms associated with loss of cortical GABA-dependent inhibition) and inclusion of more patients will help evaluate whether haplotypes are associated with a subset of ASD with specific clinical and behavioural phenotypes.

This line of research focus on the development of neural circuits and systems that underlie language processing, along with social and affiliate behaviours in an effort to understand at least some forms of ASD. 

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