Bibliographie

AS is characterized by severe mental retardation, seizures, ataxic gait and easily evoked laughter. About 70 approximately 80% of AS patients have a chromosomal/molecular deletion at 15 q11-q13, occurring exclusively in the maternally-derived chromosome 15. There have been 4 AS patients whose chromosomes 15 are paternal uniparental disomy. This biased parent-of-origin suggests that genomic imprinting may play a role in the occurrence of the syndrome. GABRB3 is located at 15 q11-q13. GABAA is a main inhibitory neurotransmitter in the central nervous system (CNS) and functions through its receptor. The beta 3 subunit, one of the components of the receptor, is present in the telephalonal cortex, hippocampus, thalamus and cerebellum, and a peak GABRB3 expression is observed during embryogenesis. This indicates that GABRB3 plays a role in CNS development, suppression of seizures and behavioral control. Since GABRB3 is encompassed within the smallest deletion among AS patients, it becomes a candidate responsible for the central nerve disturbances in AS. This smallest deletion was found in 3 AS sibs, their phenotypically normal mother and maternal grandfather in a family, suggesting that the paternally-derived deletion has no phenotypical effect in the offspring but the maternally-derived one. However, recent studies demonstrated that the mouse Gabrb3 is not involved in imprinting. The confirmation of GABRB3 to be the AS gene needs to provide direct evidence of its imprinting. Our preliminary study showed that GABRB3 was not expressed in hydatidiform mole that is composed only of the paternal genome, while it was expressed fully in normal villous tissue, suggesting that GABRB3 is paternally imprinted.