NONSPECIFIC X-LINKED SEMIDOMINANT MENTAL-RETARDATION BY MUTATIONS IN A RAB GDP-DISSOCIATION INHIBITOR

Non-specific X-linked mental retardation (MRX) is a very common disord er which affects similar to 1 in 600 males. Despite this high frequenc y, little is known about the molecular defects underlying this disorde r, mainly because of the clinical and genetic heterogeneity which is e vident from linkage studies. Recently, a collaborative study using the candidate gene approach demonstrated the presence of mutations in GDI alpha, a Rab GDP-dissociation inhibitor encoded by a gene localized i n Xq28, associated with non-specific mental retardation. GDl alpha is mainly a brain-specific protein that plays a critical role in the recy cling of Rab GTPases involved in membrane vesicular transport. The stu dy presented here was designed to assess the prevalence of mutations i n the GDla in mentally retarded patients and to discuss the clinical p henotypes observed in affected individuals, Mutation screening of the who le coding region of the GDla gene, using a combination of denaturi ng gradient gel electrophoresis and direct sequencing, was carried out in 164 patients found negative for expansions across the FRAXA GCC re peat. In addition to the nonsense mutation recently reported in MRX48, we have identified a novel missense mutation in exon 11 of the GDI al pha. gene in one familial form of non-specific mental retardation. In this family (family R), all affected males show moderate to severe men tal retardation, and the X-linked semidominant inheritance is strongly suggested by the severe phenotypes in males with respect to mildly af fected females or unaffected obligatory carriers. This study showed th at the prevalence of GDI alpha mutations in non-specific mental retard ation could be estimated to be 0.5-1%, and molecular diagnosis and gen etic counselling in some cases of nonspecific mental handicap can now be provided.