Affiliations: Manovikas Biomedical Research & Diagnostic
Centre, 482 Madudah, Plot I-24, Sector-J, Eastern Metropolitan Bypass,
Kolkata-700107, India | Manovikas Kendra Rehabilitation & Research
Institute for the Handicapped, 482 Madudah, Plot I-24, Sector-J, Eastern
Metropolitan Bypass, Kolkata-700107, India
Note: [] Corresponding author: Krishnadas Nandagopal, Ph.D., Manovikas
Biomedical Research & Diagnostic Centre, Manovikas Kendra Rehabilitation
& Research Institute for the Handicapped, 482 Madudah, Plot I-24,
Sector-J, Eastern Metropolitan Bypass, Kolkata-700107, India. Tel.: +91 033
4001 2732 extn. 235; Fax: +91 033 2442 8275; E-mail: [email protected]
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) [χ ^{2}= 31.2,
df=1, p=0.0001; D'=0.42] and 1173(C/T)-2705(T/C) [χ^{2}= 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.
Keywords: Down syndrome, mental retardation, glutamate, GluK1/GluR5/GRIK1, allelic non-disjunction, parent and stage of origin, risk
