Genomic Imprinting of the X-Linked Gene Transketolase-like 1 in Mouse and Human

Background: Imprinting of X-linked genes has been hypothesized to contribute to the 4-fold male:female sex bias in autism. This hypothesis emerged from studies of Turner syndrome, where girls with a maternal X (45,Xm) show greater propensity to social impairment and have a higher rate of autism compared to 45,Xp females and the general population. Using a mouse model for Turner syndrome to search for X-linked imprinted genes, we and others identified the X-linked Xlr3/4 locus as being imprinted. However, no imprinted orthologs of these genes have been found in humans. Since imprinted genes often exist in clusters, we expanded our search of this region of the X chromosome to identify genes that are imprinted in both mice and humans.

Objectives: To examine expression in developing brain of candidate imprinted X-linked genes and compare relative expression from parental alleles in human and mouse using quantitative PCR techniques.

Methods: Allele-specific quantitative real-time PCR was used to examine expression of X-linked genes in neonatal mouse and fetal human brain sub-regions.

Results: We have identified Transketolase-like 1 (TKTL1) as an X-linked imprinted gene in both humans and mice. In human, differential expression of TKTL1 varied from two to five-fold, showing sub-region specificity. Tktl1 expression in mouse neonatal neocortex showed higher levels in 39,Xm and 40,XY mice compared to 39,Xp and 40,XX.

Conclusions: TKTL1 exhibits imprinted expression in both humans and mice. TKTL1 codes for a transketolase enzyme, which operates in the pentose phosphate pathway (PPP). One function of the PPP is maintaining glutathione in a reduced state by reduction of NADP to NADPH. Since aberrant glutathione levels have been found associated with autistic spectrum conditions, the effect of Tktl1 expression on the state of glutathione in the developing brain is of current interest to our laboratory.