Evaluation of two X chromosomal candidate genes for Rett syndrome: glutamate dehydrogenase-2 (GLUD2) and rab GDP-dissociation inhibitor (GDI1).

The most likely cause of the Rett syndrome (RTT) is an X-linked dominant mutation lethal in hemizygous males. Previous exclusion mapping studies have identified putative regions for the RTT gene on the X chromosome. In the present study, we evaluated two candidate genes, glutamate dehydrogenase-2 (GLUD2) and rab GDP-dissociation inhibitor (GDI1/XAP-4), chosen because of their expression patterns and functions in the central nervous system and their location in the nonexcluded region of Xq. The intronless gene GLUD2, located in Xq25 and expressed in neuronal and testicular tissues, is involved in the metabolism of glutamate, a neurotransmitter reported to be elevated in the spinal fluid of RTT individuals. The GLUD2 gene was screened for mutations by Southern hybridization and by direct sequencing of polymerase chain reaction (PCR) products. The GDI1 gene in Xq28, also known as RABGDIA or XAP-4, encodes a human GDI that is expressed predominantly in neuronal and sensory tissues. All 11 exons and splice junctions of the GDI1 gene were PCR-amplified and sequenced directly or screened by single-strand conformation analysis. No mutation in either of these two genes was found in 22 RTT patients. Therefore, GLUD2 and GDI1 can be excluded as candidate genes for this syndrome.