Mutation screening and association study of the UBE2H gene on chromosome 7q32 in autistic disorder.

Autistic disorder is a severe neurodevelopmental disorder most probably caused by a complex interaction of genetic factors. Several genomewide scans identified multipoint LOD score peaks in region 7q32. In this region, UBE2H encodes an E2 enzyme of the ubiquitin-dependent proteolytic system. Mutations in another member of this system, the UBE3A gene, cause Angelman syndrome. The participation of E2 (ubiquitin-conjugating enzymes) or E3 (ubiquitin ligases) enzymes in neural development recently emerged. Given its physical location and function, we examined UBE2H as a candidate for involvement in autistic disorder. We confirmed by reverse transcription-polymerase chain reaction that the UBE2H gene was expressed in the rat and the human central nervous system. The rat UBE2H and human UBE2H deduced amino acid sequences are identical. We screened the seven exons of the UBE2H gene in autistic patients using single-strand conformation analysis. We observed a silent A-->G transition at position 336. A case-control association study was performed using this A/G polymorphism. A significant association was found between the G allele and a subgroup of autistic patients with developmental quotient higher than 30 (P=0.004). Although further studies are required, these results suggest that the UBE2H gene could be one of the 7q-susceptibility loci for autistic disorder.