Abstract
Mechanisms underlying Down syndrome (DS)-related mental retardation (MR) remain poorly understood. In trisomic offspring, non-disjunction may result in the reduction to homozygosity of a susceptibility allele inherited from a heterozygous parent. Accordingly, we sought evidence for allelic non-disjunction in the GluK1 gene that encodes the critical kainite-binding glutamate receptor subunit-5, maps to chromosome 21q22.1 in the DS critical region and is expressed in brain regions responsible for learning and memory. Three polymorphisms of GluK1 [522(A/C) rs363538; 1173(C/T) rs363430 and 2705(T/C) rs363504] were genotyped in 86 DS patient families by means of PCR-coupled RFLP assays and evaluated with respect to allele frequency, heterozygosity, linkage disequilibrium, stage and parental origin of allelic non-disjunction. We report that the distribution of allele frequencies is in Hardy-Weinberg equilibrium. Moderate heterozygosity (0.339) and a major allele frequency of 0.78 render the 1173(C/T) marker informative. Pair-wise comparisons reveal that 522(A/C)-1173(C/T) [χ2= 31.2,df= 1,p= 0.0001;D’ = 0.42] and 1173(C/T)-2705(T/C) [χ2= 18.3,df= 1,p= 0.0001;D’ = 0.34] are in significant linkage disequilibrium of weak magnitude. The estimated ratio of meiosis-I to meiosis-II errors arising from allelic non-disjunction of 1173(C/T) is 4:1 in maternal cases and 2:1 in paternal cases. Studies including additional markers and patient samples are warranted to further substantiate present findings.
Highlights
Down syndrome (DS) occurs due to non-disjunction of chromosome 21 and is the leading genetic cause of mental retardation (MR) [12,27,33]
We report that distribution of allele frequencies are in Hardy-Weinberg equilibrium and pair-wise combinations of alleles are in significant linkage disequilibrium of weak magnitude
This study presents evidence for allelic non-disjunction at 1173(C/T) in the GluK1 gene that is an important candidate for genetic studies on DS-related MR
Summary
Down syndrome (DS) occurs due to non-disjunction of chromosome 21 and is the leading genetic cause of mental retardation (MR) [12,27,33]. Ghosh et al / A study of GluK1 kainate receptor polymorphisms in Down syndrome reveals allelic non-disjunction at 1173(C/T). The human GluK1/GRIK1/GluR5 gene codes for the critical subunit-5 of glutamate receptors that bind kainate [1,7], maps to chromosome 21q22.1 [17] and spans 400 kb with 18 exons [1] (Fig. 1). A search of human (T1Dbase) [3,23] and murine (Gene Novartis Foundation) [3] databases reveals region-specific expression of GluK1 mRNA in the cerebellum, striatum, caudate nucleus, hippocampus, amygdala and the cortex. The 522(A/C) [rs363538] transversion in exon 3 and the 1173(C/T) [rs363430] transition in exon 8 result in conservative changes in the codons for the amino-acid residues T174 and D391, respectively [25] These residues are located in the extra-cellular ligand-binding loop [32]. The estimated ratio of meiosis-I to meiosis-II errors is 4:1 in maternal cases and 2:1 in paternal cases suggesting varying risk for non-disjunction
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