Specific Clinical and Brain MRI Features in Mentally Retarded Patients with Mutations in the Oligophrenin-1 Gene

Service de Pédiatrie, HCL, Centre Hospitalier Lyon Sud, 69395 Pierre-Bénite, France.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 02/2004; 124A(4):364-71. DOI: 10.1002/ajmg.a.20422
Source: PubMed


Oligophrenin-1 (OPHN-1) gene disruption is known as responsible for so called "non-specific" X-linked mental retardation (MR) Billuart et al. [1998: Nature 392:923-926]. In order to search for a possible specific clinical and radiological profile for mutation in the OPHN-1 gene, clinical and 3D brain MRI studies were performed in the two families with a known mutation in OPHN-1 reported so far: a 19-year-old female with an X;12 balanced translocation encompassing OPHN-1, and four affected males of family MRX60 sharing a frameshift mutation in OPHN-1. Clinical data shared by affected individuals were neonatal hypotonia with motor delay but no obvious ataxia, marked strabismus, early onset complex partial seizures, and moderate to severe MR. Brain MRIs performed in three individuals exhibited a specific vermian dysgenesis including an incomplete sulcation of anterior and posterior vermis with the most prominent defect in lobules VI and VII. In addition, a non-specific cerebral cortico-subcortical atrophy was also observed. These clinical and radiological features suggest a distinct clinico-radiological syndrome. These preliminary data need to be confirmed in other families and will be helpful for further targeted mutation screening of the OPHN-1 gene in male patients with similar clinico-radiological features. In addition, OPHN-1 inactivation should be considered as a relevant model of developmental vermis disorganization, leading to a better understanding of the possible role of the cerebellum in MR.

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    • "Thus, it is conceivable that on one hand OPHN1 might play an important role in synapse maturation and circuit wiring during early development, on the other hand the regulated OPHN1 synthesis could operate during adulthood to weaken synapses in response to behaviorally relevant stimuli. In light of the previously reported role for LTD in behavioral flexibility and novelty detection (Kemp and Manahan-Vaughan, 2007; Lü scher and Huber, 2010), and the association of OPHN1 loss of function with altered social behavior and novelty-driven hyperactivity (des Portes et al., 2004; Khelfaoui et al., 2007; Zanni et al., 2005), the requirement for OPHN1 in mGluR-LTD could offer an intriguing potential explanation for some of the behavioral deficits exhibited by OPHN1 patients. "
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    ABSTRACT: Activation of group I metabotropic glutamate receptors leads to long-term depression (mGluR-LTD). Alterations in this form of plasticity have been linked to drug addiction and cognitive disorders. A key characteristic of mGluR-LTD is its dependence on rapid protein synthesis; however, the identities of the proteins mediating LTD remain elusive. Here, we identify the X-linked mental retardation protein OPHN1 as a molecule essential for mGluR-LTD in the hippocampus. mGluR-LTD induction elicits rapid dendritic OPHN1 synthesis, which is dependent on mGluR1 activation and independent of fragile X mental retardation protein (FMRP). This response is essential for mGluR-LTD, as acute blockade of OPHN1 synthesis impedes LTD. mGluR-induced OPHN1 mediates LTD and associated persistent decreases in surface AMPARs via interactions with endophilin A2/3. Importantly, this role of OPHN1 is separable from its effects on basal synaptic strength, which require OPHN1's Rho-GAP activity and interaction with Homer1b/c. Thus, our data establish a role for rapid OPHN1 synthesis in mGluR-LTD. VIDEO ABSTRACT:
    Full-text · Article · Oct 2011 · Neuron
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    • "A consistent dilatation of the lateral cerebral ventricles and mild cortical atrophy was also present. A similar clinico-radiological phenotype (Figure 1a-c) was found in the affected males of a family carrying a single nucleotide deletion in exon 19 of the OPHN1, initially diagnosed with non-syndromic X-linked mental retardation [9]. Another deletion comprising exon 19 of the OPHN1 gene, was identified in a family with five affected males showing moderate to severe mental retardation, infantile-onset epilepsy, hypotonia, strabismus and ataxia. "
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    ABSTRACT: X-linked disorders with cerebellar dysgenesis (XLCD) are a genetically heterogeneous and clinically variable group of disorders in which the hallmark is a cerebellar defect (hypoplasia, atrophy or dysplasia) visible on brain imaging, caused by gene mutations or genomic imbalances on the X-chromosome. The neurological features of XLCD include hypotonia, developmental delay, intellectual disability, ataxia and/or other cerebellar signs. Normal cognitive development has also been reported. Cerebellar dysgenesis may be isolated or associated with other brain malformations or multiorgan involvement. There are at least 15 genes on the X-chromosome that have been constantly or occasionally associated with a pathological cerebellar phenotype. 8 XLCD loci have been mapped and several families with X-linked inheritance have been reported. Recently, two recurrent duplication syndromes in Xq28 have been associated with cerebellar hypoplasia. Given the report of several forms of XLCD and the excess of males with ataxia, this group of conditions is probably underestimated and families of patients with neuroradiological and clinical evidence of a cerebellar disorder should be counseled for high risk of X-linked inheritance.
    Full-text · Article · May 2011 · Orphanet Journal of Rare Diseases
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    • "The distinction between syndromic or non-specific forms of MR is somehow vanishing and some MR cases have been reconsidered after clinical re-evaluation of patients. For example, the non-specific MR gene mental retardation associated with null mutations in Oligophrenin1 (OPHN1) was originally described as non-syndromic (3), but later investigations suggested a syndromic XLMR associated with cerebellar hypoplasia and ventricular dilatation (4–6). We have recently reported that the Ophn1 gene loss of function in mouse displays similarities to the human pathology, apart from the cerebellar hypoplasia, results in dendritic spine immaturity and in altered pre-synaptic function with a reduction of paired-pulse facilitation in CA1 hippocampus (7). "
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    ABSTRACT: The patho-physiological hypothesis of mental retardation caused by the deficiency of the RhoGAP Oligophrenin1 (OPHN1), relies on the well-known functions of Rho GTPases on neuronal morphology, i.e. dendritic spine structure. Here, we describe a new function of this Bin/Amphiphysin/Rvs domain containing protein in the control of clathrin-mediated endocytosis (CME). Through interactions with Src homology 3 domain containing proteins involved in CME, OPHN1 is concentrated to endocytic sites where it down-regulates the RhoA/ROCK signaling pathway and represses the inhibitory function of ROCK on endocytosis. Indeed disruption of Ophn1 in mice reduces the endocytosis of synaptic vesicles and the post-synaptic α-amino-3-hydroxy-5-methylisoazol-4-propionate (AMPA) receptor internalization, resulting in almost a complete loss of long-term depression in the hippocampus. Finally, pharmacological inhibition of this pathway by ROCK inhibitors fully rescued not only the CME deficit in OPHN1 null cells but also synaptic plasticity in the hippocampus from Ophn1 null model. Altogether, we uncovered a new patho-physiological mechanism for intellectual disabilities associated to mutations in RhoGTPases linked genes and also opened new directions for therapeutic approaches of congenital mental retardation.
    Full-text · Article · May 2009 · Human Molecular Genetics
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