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

ArticleinAmerican Journal of Medical Genetics Part A 124A(4):364-71 · February 2004with11 Reads
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.
    • "Known developmental syndromes, particularly those involving ID, are frequently identified based upon shared phenotypic characteristics beyond ID, which may reflect the pleiotropic effects of a recurrently mutated gene [31][32][33][34][35]. Moving beyond a mutation in a single gene, we reasoned that if a functional enrichment identified among the copy number variant genes within a given set of patients identifies a common biological pathway perturbed within those patients , then the consequence of perturbing the same pathway may yield a similar set of phenotypes. "
    [Show abstract] [Hide abstract] ABSTRACT: Readily-accessible and standardised capture of genotypic variation has revolutionised our understanding of the genetic contribution to disease. Unfortunately, the corresponding systematic capture of patient phenotypic variation needed to fully interpret the impact of genetic variation has lagged far behind. Exploiting deep and systematic phenotyping of a cohort of 197 patients presenting with heterogeneous developmental disorders and whose genomes harbour de novo CNVs, we systematically applied a range of commonly-used functional genomics approaches to identify the underlying molecular perturbations and their phenotypic impact. Grouping patients into 408 non-exclusive patient-phenotype groups, we identified a functional association amongst the genes disrupted in 209 (51%) groups. We find evidence for a significant number of molecular interactions amongst the association-contributing genes, including a single highly-interconnected network disrupted in 20% of patients with intellectual disability, and show using microcephaly how these molecular networks can be used as baits to identify additional members whose genes are variant in other patients with the same phenotype. Exploiting the systematic phenotyping of this cohort, we observe phenotypic concordance amongst patients whose variant genes contribute to the same functional association but note that (i) this relationship shows significant variation across the different approaches used to infer a commonly perturbed molecular pathway, and (ii) that the phenotypic similarities detected amongst patients who share the same inferred pathway perturbation result from these patients sharing many distinct phenotypes, rather than sharing a more specific phenotype, inferring that these pathways are best characterized by their pleiotropic effects.
    Full-text · Article · Mar 2015
    • "We used the Human Splicing Finder server to estimate the relative strength of the canonical and the alternative 5' donor sequences and found that they are comparable. In fact the HSF matrices estimate a consensus value of 84.38 and 83.08 for the canonical and alternative donor sites, respectively (Desmet et al., 2009). HSF also reports the 5' score predicted with the Maximum Entropy modeling method (Yeo and Burge, 2004) that is 7.52 for the canonical donor site and 6.06 for the alternative site. "
    [Show abstract] [Hide abstract] ABSTRACT: We observed a three-generation family with two maternal cousins and an uncle affected by mental retardation (MR) with cerebellar hypoplasia. X-linked inheritance and the presence of cerebellar malformation suggested a mutation in the OPHN1 gene. In fact, mutational screening revealed a 2-bp deletion that abolishes a donor splicing site, resulting in the inclusion of the initial 48 nucleotides of intron 7 in the mRNA. This mutation determines the production of a mutant oligophrenin 1 protein with 16 extra amino acids inserted in-frame in the N-terminal BAR (Bin1/amphiphysin/Rvs167) domain. This is the first case of a mutation in OPHN1 that does not result in the production of a truncated protein or in its complete loss. OPHN1 (ARHGAP41) encodes a GTPase-activating (GAP) protein belonging to the GRAF subfamily characterized by an N-terminal BAR domain, followed by a pleckstrin-homology (PH) domain and the GAP domain. GRAF proteins play a role in endocytosis and are supposed to dimerize via their BAR domain, that induces membrane curvature. The extra 16 amino acids cause the insertion of 4.4 turns in the third alpha-helix of the BAR domain and apparently impair the protein function. In fact, the clinical phenotype of these patients is identical to that of patients with loss-of-function mutations.
    Full-text · Article · Nov 2011
    • "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. "
    [Show abstract] [Hide abstract] ABSTRACT: Video 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.
    Full-text · Article · Oct 2011
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