Title

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

Date of Completion

January 2010

Keywords

Biology, Molecular|Biology, Genetics|Biology, Neurobiology

Degree

Ph.D.

Abstract

Genomic imprinting is defined as differential allele expression based on parental origin. 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, X m) show greater propensity to social impairment and have a higher rate of autism compared to paternal X (45, Xp) females and the general population. Through the use of murine models, the X-linked Xlr3/4 locus and Rhox5 have been identified as imprinted. However, no imprinted orthologs of these genes have been found in humans. Therefore, the search was expanded to identify X-linked genes that are imprinted in both mouse and human. ^ Allele-specific quantitative real-time PCR was used to examine expression of candidate genes in developing brain. As a result, we have identified Transketolase-like 1 (Tktl1) as an X-linked imprinted gene. 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 was studied in the developing brain. In addition, Tktl1 allows for another opportunity to determine the mechanism of X-linked genomic imprinting, which is of current interest to our laboratory. ^