Mutation screening in Rett syndrome patients

Rett syndrome (RTT) was first described in 1966. Its biological and genetic foundations were not clear until recently when Amir ef al reported that mu tations in the IMECP2 gene were detected in around 50% of RTT patients. In this study, we have screened the MECP2 gene for mutations in our RTT materi al, including nine familial cases (19 Rett girls) and 59 sporadic cases. A total of 27 sporadic RTT patients were found to have mutations in the MECP2 gene, but no mutations were identified in our RTT families. In order to ad dress the possibility of further X chromosomal or autosomal genetic factors in RTT,we evaluated six candidate genes for RTT selected on clinical, path ological, and genetic grounds: UBE1 (human ubiquitin activating enzyme Fl, located in chromosome Xp11.23), UBE2I (ubiquitin conjugating enzyme E2I, ho mologous to yeast UBC9, chromosome 16p13.3), GdX (ubiquitin-like protein, c hromosome Xq28), SOX3 (SRY related HMG box gene: 3, chromosome Xq26-q27), G ABRA3 (gamma-aminobutyric acid type A receptor alpha 3 subunit, chromosome Xq28), and CDR2 (cerebellar degeneration related autoantigen 2, chromosome 16p12-p13.1). No mutations were detected in the coding regions of these six genes in 10 affected subjects and, therefore, alterations in the amino aci d sequences of the encoded proteins can be excluded as having a causative r ole in RTT. Furthermore, gene expression of MECP2, GdX, GABRA3, and L1CAM ( L1 cell adhesion molecule) was also investigated by in situ hybridisation. No gross differences were observed in neurones of several brain regions bet ween normal controls and Rett patients.