Human Molecular Genetics, Vol 7, 1311-1315, Copyright © 1998 by Oxford University Press
T Bienvenu, V des Portes, A Saint Martin, N McDonell, P Billuart, A Carrie, MC Vinet, P Couvert, D Toniolo, HH Ropers, C Moraine, H van Bokhoven, JP Fryns, A Kahn, C Beldjord and J Chelly
Non-specific X-linked mental retardation (MRX) is a very common disorder
which 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 evident
from linkage studies. Recently, a collaborative study using the candidate
gene approach demonstrated the presence of mutations in GDIalpha, a Rab
GDP-dissociation inhibitor encoded by a gene localized in Xq28, associated
with non-specific mental retardation. GDIalpha is mainly a brain-specific
protein that plays a critical role in the recycling of Rab GTPases involved
in membrane vesicular transport. The study presented here was designed to
assess the prevalence of mutations in the GDIalpha in mentally retarded
patients and to discuss the clinical phenotypes observed in affected
individuals. Mutation screening of the whole coding region of the GDIalpha
gene, using a combination of denaturing gradient gel electrophoresis and
direct sequencing, was carried out in 164 patients found negative for
expansions across the FRAXA GCC repeat. In addition to the nonsense
mutation recently reported in MRX48, we have identified a novel missense
mutation in exon 11 of the GDIalpha gene in one familial form of
non-specific mental retardation. In this family (family R), all affected
males show moderate to severe mental retardation, and the X-linked
semidominant inheritance is strongly suggested by the severe phenotypes in
males with respect to mildly affected females or unaffected obligatory
carriers. This study showed that the prevalence of GDIalpha mutations in
non-specific mental retardation could be estimated to be 0.5-1%, and
molecular diagnosis and genetic counselling in some cases of non-specific
mental handicap can now be provided.
ARTICLES
Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor
INSERM U129, Institut Cochin de Genetique Moleculaire, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France. bienvenu@cochin.inserm.fr
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