Oligophrenin 1 mutations frequently cause X-linked mental retardation with cerebellar hypoplasia.
BACKGROUND
Mutations of oligophrenin 1, one of the first genes identified in nonspecific X-linked mental retardation (MRX), have been described in patients with moderate to severe cognitive impairment and predominant cerebellar hypoplasia, in the vermis.


OBJECTIVE
To further delineate the phenotypic and mutational spectrum of the syndrome, by screening oligophrenin 1 in two cohorts of male patients with mental retardation (MR) with or without known posterior fossa anomalies.


METHODS
Clinical examination, cognitive testing, MRI studies, and mutational analysis (denaturing gradient gel electrophoresis and direct sequencing) on blood lymphocytes were performed in 213 unrelated affected individuals: 196 patients classified as MRX and 17 patients with MR and previously detected cerebellar anomalies.


RESULTS
Four novel oligophrenin 1 mutations were identified. In the MRX group, two nonsense mutations were detected. In the MR group, two mutations were found: a deletion of exons 16 to 17 and a splice site mutation. All patients shared characteristic clinical, radiologic, and distinctive features with a degree of intrafamilial variability in motor and cognitive deficits.


CONCLUSIONS
Oligophrenin 1 mutations were found in 12% (2/17) of individuals with mental retardatin and known cerebellar anomalies and in 1% (2/196) of the X-linked mental retardation group.
Zanni
G
G
University of Paris 5 René Descartes, INSERM Unité 567, CNRS UMR8104, Paris, France.
Saillour
Y
Y
Nagara
M
M
Billuart
P
P
Castelnau
L
L
Moraine
C
C
Faivre
L
L
Bertini
E
E
Durr
A
A
Guichet
A
A
Rodriguez
D
D
des Portes
V
V
Beldjord
C
C
Chelly
J
J
D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D002526:Cerebellar Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D002531:Cerebellum / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005146:Facial Asymmetry / Q000175:diagnosis / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics*; D017353:Gene Deletion; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D038901:X-Linked Intellectual Disability / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009421:Nervous System Malformations / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics
D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C111952:OPHN1 protein, human; D022821:RNA Splice Sites