Wednesday, October 25, 2017

OPHN1 syndrome

Inspired by a patient.  Another victory for whole exome sequencing.

Nakano-Kobayashi A, Tai Y, Nadif Kasri N, Van Aelst L. The X-linked mental retardation protein OPHN1 interacts with Homer1b/c to control spine endocytic zone positioning and expression of synaptic potentiation. J Neurosci. 2014 Jun 25;34(26):8665-71.

At glutamatergic synapses, local endocytic recycling of AMPA receptors (AMPARs) is important for the supply of a mobile pool of AMPARs required for synaptic potentiation. This local recycling of AMPARs critically relies on the presence of an endocytic zone (EZ) near the postsynaptic density (PSD). The precise mechanisms that couple the EZ to the PSD still remain largely elusive, with the large GTPase Dynamin-3 and the multimeric PSD adaptor protein Homer1 as the two main players identified. Here, we demonstrate that a physical interaction between the X-linked mental retardation protein oligophrenin-1 (OPHN1) and Homer1b/c is crucial for the positioning of the EZ adjacent to the PSD, and present evidence that this interaction is important for OPHN1's role in controlling activity-dependent strengthening of excitatory synapses in the rat hippocampus. Disruption of the OPHN1-Homer1b/c interaction causes a displacement of EZs from the PSD, along with impaired AMPAR recycling and reduced AMPAR accumulation at synapses, in both basal conditions and conditions that can induce synaptic potentiation. Together, our findings unveil a novel role for OPHN1 as an interaction partner of Homer1b/c in spine EZ positioning, and provide new mechanistic insight into how genetic deficits in OPHN1 can lead to impaired synapse maturation and plasticity.

Oligophrenin-1 syndrome
The OPHN1 syndrome (MIM 300486) was first described in a 12 year-old girl, carrier of a de novo translocation t(X;12)(q11;q15) which was found to disrupt the Oligophrenin-1 (OPHN1) gene at Xq12 and encodes a RhoGTPase activating protein (RhoGAP) involved in synaptic morphogenesis and function. The girl had congenital hypotonia, severe developmental delay, moderate cognitive impairment, early-onset complex partial seizures and bilateral divergent strabismus and dysmetria. At a later reevaluation, Brain MRI showed a posterior vermis dysgenesis including partial agenesis of lobules VI and VII associated with right vermian parasagittal cleft and mild cerebellar hemisphere hypoplasia. A consistent dilatation of the lateral cerebral ventricles and mild cortical atrophy was also present. A similar clinico-radiological phenotype 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. 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. Cryptorchidism and genital hypoplasia were present in all affected males. Neuroradiological findings included cortical atrophy, enlargement of the cerebral ventricles, bilateral hypoplasia of the head of the caudate nucleus, lower vermis and cerebellar hemisphere hypoplasia. One carrier sister had mild learning disabilities and strabismus but her brain MRI was normal. A stop mutation in exon 3 and an 8 base-pair insertion in exon 9 of the OPHN1 gene were identified in two other families with a similar phenoype. In a family with a 2 base-pair deletion in exon 8 of OPHN1 leading to a premature stop codon, the affected males showed developmental and cognitive delay with IQ ranging from 46 to 54, strabismus, early-onset generalized tonic-clonic seizures, abnormal behaviour and a characteristic facial phenotype with long face, prominent forehead, infraorbital creases, deep set eyes, upturned philtrum and large ears. The obligate carrier females showed only mild cognitive impairment and subtle facial changes. Brain MRI studies performed in the propositus at age 3 months showed underdeveloped frontal lobes, loss of brain volume with enlarged lateral ventricles, prominent subarachnoid spaces and a particular square shape of the frontal horns. Cerebellar hypoplasia and vermis dysgenesis with a large cisterna magna and a retrocerebellar cyst were noted .

A de novo translocation disrupting the OPHN1 gene in a female patient and intragenic deletions of OPHN1 detected by arrayCGH, in a male patient and in two families in which affected individuals all showed the characteristic clinico-radiological phenotype associated with OPHN1 syndrome were also reported. In one family with six affected males with intellectual deficit, minor facial anomalies, cubitus valgus, with or without sensorineural deafness, a deletion of exons 16-18 in the OPHN1 gene was identified. Screening OPHN1 in a large cohort of patients led to the identification of mutations in 12% of individuals with intellectual deficit and cerebellar hypoplasia, suggesting that the screening of this gene should be implemented in boys with vermis hypoplasia, enlarged cerebral ventricles and developmental delay.

Courtesy of a colleague

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