Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor

Non-specific X-linked mental retardation (MRX) is a very common disorderwhich affects approximately 1 in 600 males. Despite this high frequency,little is known about the molecular defects underlying this disorder,mainly because of the clinical and genetic heterogeneity which is evidentfrom linkage studies. Recently, a collaborative study using the candidategene approach demonstrated the presence of mutations in GDIalpha, a RabGDP-dissociation inhibitor encoded by a gene localized in Xq28, associatedwith non-specific mental retardation. GDIalpha is mainly a brain-specificprotein that plays a critical role in the recycling of Rab GTPases involvedin membrane vesicular transport. The study presented here was designed toassess the prevalence of mutations in the GDIalpha in mentally retardedpatients and to discuss the clinical phenotypes observed in affectedindividuals. Mutation screening of the whole coding region of the GDIalphagene, using a combination of denaturing gradient gel electrophoresis anddirect sequencing, was carried out in 164 patients found negative forexpansions across the FRAXA GCC repeat. In addition to the nonsensemutation recently reported in MRX48, we have identified a novel missensemutation in exon 11 of the GDIalpha gene in one familial form ofnon-specific mental retardation. In this family (family R), all affectedmales show moderate to severe mental retardation, and the X-linkedsemidominant inheritance is strongly suggested by the severe phenotypes inmales with respect to mildly affected females or unaffected obligatorycarriers. This study showed that the prevalence of GDIalpha mutations innon-specific mental retardation could be estimated to be 0.5-1%, andmolecular diagnosis and genetic counselling in some cases of non-specificmental handicap can now be provided.