The human Oligophrenin-1 (OPHN1) gene codes for the OPHN1 protein, which is a Rho-GTPase-activating protein that stimulates GTP hydrolysis of members of the Rho family. These Rho proteins play an important role in signal transduction cascades, especially in spine morphogenesis and synapse development. One of these Rho proteins, RhoA, is especially important in the growth and stabilization of dendritic spines. Apart from its role in dendritic spine maturation, OPHN1 has also been shown to play a critical role in the activity-dependent maturation and plasticity of excitatory synapses by controlling their structural and functional stability. In fact, mice deficient in OPHN1 have been shown to have immature dendritic spines, altered synaptic function, ventricular enlargement, and impaired spatial memory.
Mutations in the OPHN1 gene result in a syndromic form of X-linked Mental Retardation, characterized by cerebellar hypoplasia and variable dysmorphic features.
The OPHN1 gene spans a length of 391 kb on chromosome Xq12. The 25 exons of this gene translate to a protein consisting of 802 amino acids. The gene is expressed mostly in the fetal and adult neuronal and glial cells. During adulthood, expression in the brain is enriched in the hippocampus, the olfactory bulb, and the cerebellum. Recent studies have shown that the transcript undergoes multiple post-translational modifications, such as A-to-I RNA editing and alternative splicing in these tissues. Structurally, the protein consists of at least three different domains; an N-terminal Bin/Amphiphysin/Rvs (BAR) domain that binds curved membranes, a Pleckstrin homology domain that is involved in conferring membrane-binding specificity, and a central RhoGAP domain that able to stimulate the GTPase activity of Rho proteins such as RhoA, Rac1 and Cdc42. These domains are followed by three C-terminal proline-rich sequences, which are putative SH3-binding sites.
There are more than 30 variants reported in the OPHN1 gene that are associated with a phenotype of intellectual disability.
Al-Owain et al (2011) described a large Saudi family of four brothers and one sister affected with XLMR associated with cerebellar hypoplasia, strabismus, and distinct facial features, with a novel mutation in the OPHN1 gene. Multiple Ligation Probe Amplification (MLPA) analysis detected a hemizygous deletion of at least exons 7-15 in the OPHN1 gene in two of the affected siblings, which was subsequently identified in the rest of the affected patients too. Array CGH, used to identify the breakpoints of this intragenic deletion, delineated an approximately 68 kb stretch covering exons 7-15 and nearly half of intron 15. The female carrier was affected only mildly, and had a normal random X-inactivation pattern.