MOLECULAR BIOLOGY LAB

Mental retardation is significantly more frequent in males than in females due to X linked pattern of inheritance which shows that X linked gene defects play an important role in the etiology of mental retardation. X linked mental retardation accounts for 10% of mental retardation thus rivaling chromosome aberrations as cause of mental retardation. It is estimated that two thirds of X linked mental retardation cases are non-syndromic. However it is believed that the molecular basis for cutting a boundary between syndromic and non-syndromic forms of mental retardation is difficult as the first identified fragile X syndrome was classified as non-syndromic but now it is classified as the most frequent syndromic XLMR. In Non syndromic XLMR only 50% of the causative gene defects have been identified which opens a new realm of field yet unexplored. In contrast to the autosomal cause of mental retardation in which the recurrence risks are low the X linked cause is of importance in the recurrence risk in the families. Research in XLMR is of importance due to two observations one is that there are excess of males than females and the excess is approximately 30%. Second is that there are number of multigenerational pedigrees observed where mental retardation shows X linked patterns of inheritance. Which means there are excess of males affected, female carriers are less seriously affected or are normal and there is no male to male transmission. Although genes that are associated with mental retardation are concentrated in regions of the distal short arm (Xp22.1-p21.3), proximal short arm (Xp11), and distal long arm (Xq28), XLMR genes are seen to be distributed throughout the X chromosome. It is reported that genes that cause syndromic XLMR usually code for proteins with broad range of molecular targets that include regulators of transcription and translation or protein kinases involved in intracellular signaling, whereas genes that cause non syndromic XLMR encode for proteins that specific tasks such as proteins involved in shuttling of synaptic vesicles or the establishment of synaptic contacts. Majority of the single genes that give rise to mental retardation are on the X chromosome. Identifying the cause of mental retardation may have a significant impact on prenatal screening and genetic counseling Cryptic unbalanced subtelomeric rearrangements are know to cause significant proportion of idiopathic mental retardation. Conventional cytogenetic analysis has about 400-500 band resolution and even the high resolution banding has a limited resolution of about 850. However, these methods suffer from either limited resolution or limited throughput.

In comparison, Comparative Genomic Hybridization microarray (aCGH), with a high resolution offers a rapid, genome-wide technique for detecting chromosomal imbalances. The diagnostic yield of CGH has been shown to be higher than subtelomeric FISH screening. Comparative genomic hybridization is a technique for screening whole genome imbalances. The usefulness and sensitivity of comparative genomic hybridization highlighted in identifying genomic imbalances in patients with normal G banded karyotypes. Identification of molecular defect in different cases of mental retardation is expected to lead to its better classification, diagnosis and genetic counseling to the XLMR families. Initial study by Institute of Bioinformatics on a manually curated functional annotation of human X chromosome using bioinformatics tools such as comparative genomic analysis have identified 43 novel gene. This search has instigated our interest on the role of the X linked genes and especially the genes that play a pivotal role in brain function and the role of X chromosome gene defects in mental retardation for therapeutic modalities.