Alternative titles; symbols
HGNC Approved Gene Symbol: OPHN1
Cytogenetic location: Xq12 Genomic coordinates (GRCh38): X:68,042,344-68,433,841 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq12 | Intellectual developmental disorder, X-linked syndromic, Billuart type | 300486 | X-linked recessive | 3 |
OPHN1 encodes a Rho GTPase-activating protein (RhoGAP; see 602732) whose loss of function is associated with Billuart-type X-linked syndromic intellectual developmental disorder (MRXSBL; 300486) (Kasri et al., 2009).
Using a probe that detected a junction fragment from a female patient with mild mental retardation and an X;12 balanced translocation (Bienvenu et al., 1997), Billuart et al. (1998) identified an EST with similarities to human, mouse, and C. elegans ESTs. Using this EST, they isolated a novel human fetal brain cDNA encoding an 802-amino acid protein, which they termed oligophrenin-1. The protein contains a domain typical of RhoGAPs, which modulate cytoskeletal changes. Northern blot analysis demonstrated greatest abundance of the 7.5-kb oligophrenin-1 transcript in RNA from human fetal brain. Fluorescence in situ hybridization indicated that the X;12 translocation breakpoint identified in the patient mapped within the second intron of the OPHN1 gene, resulting in a displacement on the derivative 12 of the first 2 exons, 1 of which contained a putative translation initiation codon. RT-PCR experiments demonstrated absence of expression of the OPHN1 gene.
Khelfaoui et al. (2009) noted that OPHN1 contained an N-terminal BAR (Bin/amphiphysin/Rvs) domain, pleckstrin-homology (PH) domain, central RhoGAP domain, and 3 C-terminal proline-rich regions containing multiple SH3 binding domains.
Billuart et al. (1998) determined that the OPHN1 gene contains 25 exons.
By genomic sequence analysis, Billuart et al. (1998) mapped the OPHN1 gene to chromosome Xq12.
Using in situ hybridization, Billuart et al. (1998) found that the mouse Ophn1 gene is expressed during development at low levels in all tissues and at a higher level in all parts of the developing neuroepithelium of the neural tube. In later stages of differentiation and in the mature brain, a significant level of expression is visible in different brain structures. In vitro analysis showed that oligophrenin-1, a RhoGAP protein, specifically stimulates GTP hydrolysis of members of the Rho subfamily, thereby negatively regulating Rho-GTPase activity. Inactivation of a RhoGAP protein might cause constitutive activation of GTPase targets, which is known to affect cell migration and outgrowth of axons and dendrites in vivo. Billuart et al. (1998) suggested an association between cognitive impairment and a defect in a signaling pathway that depends on Rho GTPases.
Using RNA interference (RNAi) and antisense RNA, Govek et al. (2004) found that downregulation of oligophrenin-1 in CA1 neurons in rat hippocampal slices resulted in a significant decrease in dendritic spine length (ranging from a 12 to 18% decrease). In cell culture, expression of OPHN1 decreased global levels of active Rho-GTPases, and decreased OPHN1 levels resulted in an increase in RhoA (165390) and Rho-kinase activities. Increased RhoA activity resulted in decreased dendritic spine length, and inhibition of Rho-kinase restored spine length. The findings suggested that endogenous oligophrenin-1 acts normally to repress the Rho signaling pathway to maintain dendritic spine length, and that when the repression is relieved by loss of oligophrenin-1, there is a subsequent increase in Rho-kinase activity, causing a reduction in spine length.
By temporally and spatially manipulating Ophn1 expression in cultured rat hippocampal neurons, Kasri et al. (2009) showed that Ophn1 played a key role in activity-dependent maturation and plasticity of excitatory synapses. Ophn1 localization and its function in excitatory synapses depended on synaptic activity and NMDA receptor (see GRIN1; 138249) activation. Ophn1 also regulated the stability of AMPA receptors (see GRIA1; 138248) in a RhoGAP-dependent manner. Defective Ophn1 signaling resulted in destabilization of synaptic AMPA receptors and spine structure, leading to impaired plasticity and eventual loss of spines and NMDA receptors.
By yeast 2-hybrid screening of a fetal brain cDNA library using human OPHN1 as bait, Khelfaoui et al. (2009) found that proteins involved in clathrin-mediated endocytosis (CME), such as amphiphysin II (BIN1; 601248), endophilin B1 (SH3GLB1; 609287), endophilin B2 (SH3GLB2; 609288), and CIN85 (SH3KBP1; 300374), interacted with OPHN1. GST pull-down assays confirmed the interactions through the OPHN1 proline-SH3 binding sites. Through interaction with proteins involved in CME, OPHN1 was concentrated to endocytic sites where it downregulated the RhoA (165390)/ROCK1 (601702) signaling pathway and repressed the inhibitory function of ROCK1 on endocytosis. Disruption of Ophn1 in mice reduced endocytosis of synaptic vesicles and the postsynaptic AMPA receptor (see GRIA1, 138248) internalization, resulting in almost a complete loss of NMDA-dependent long-term depression in the hippocampus. Pharmacologic inhibition of this pathway by ROCK1 inhibitors fully rescued not only the CME deficit in OPHN1-null cells but also synaptic plasticity in the hippocampus from Ophn1-null mice.
In a family with X-linked intellectual developmental disorder (MRXSBL; 300486), originally designated MRX60, Billuart et al. (1998) identified a 1-bp deletion in the OPHN1 gene (300127.0001).
Tentler et al. (1999) reported 2 sisters of Finnish descent with a normal 46,XY karyotype and a distinctive syndrome that included psychomotor retardation, complete androgen insensitivity, seizures, ataxia, and hypotonia. Cranial MRI scans showed enlargement of the cerebral ventricles and cerebellar hypoplasia. Both sisters had a deletion on the X chromosome which extended from the 5-prime end of the AR gene to a region approximately 80 kb proximal to the EPLG2 gene (300035); the OPHN1 gene and 1.1 Mb of flanking DNA were deleted. The findings on cranial MRI supported the involvement of the oligophrenin-1 gene in specific morphologic abnormalities of the brain.
Zanni et al. (2005) identified 4 different novel mutations in the OPHN1 gene in 2 (12%) of 17 unrelated males with mental retardation and known cerebellar anomalies and in 2 (1%) of 196 unrelated males with X-linked mental retardation without previous brain imaging studies. Retrospective imaging studies, when possible, detected cerebellar hypoplasia in the latter patients, indicating that OPHN1 mutations are associated with a syndromic form of X-linked mental retardation with cerebellar hypoplasia.
In affected members of a Saudi family with syndromic X-linked mental retardation, Al-Owain et al. (2011) identified an intragenic 68-kb deletion spanning exons 7 to 15 in the OPHN1 gene (300127.0006).
Bedeschi et al. (2008) reported a 20-year-old man with severe psychomotor retardation, lack of expressive language, and seizures associated with an 800-kb interstitial duplication at chromosome Xq12-q13.1, encompassing the OPHN1, YIPF6 (300996), and STARD8 (300689) genes. He had microcephaly and dysmorphic facies with a sloping forehead, thick eyebrows, apparent hypertelorism, downslanting palpebral fissures, narrow nasal bridge, broad nasal tip, long philtrum, thin upper lip, thick lower lip, a single mandibular incisor, receding chin, and a prominent abnormally shaped left ear. He also had proximal joint laxity and scoliosis secondary to trunk hypotonia, leg asymmetry, muscular hypotrophy, and hyperreflexia. Brain MRI showed normal posterior cranial fossa findings and ventricular size with abnormalities of the supratentorial white matter, corpus callosum, posterior arms of internal capsules, and pontine tegmentum. His unaffected mother carried the duplication and showed skewed X-inactivation. Bedeschi et al. (2008) noted that the dysmorphic phenotype and MRI findings in their patient were not consistent with those reported for patients with OPHN1 mutations.
The pathophysiologic hypothesis of mental retardation caused by the deficiency of OPHN1 relies on the well-known functions of Rho GTPases on neuronal morphology (i.e., dendritic spine structure). Khelfaoui et al. (2007) generated Ophn1-null mice and observed behavior defects in spatial memory together with impairment in social behavior, lateralization, and hyperactivity. In cultured mouse cells, inactivation of Ophn1 function increased the density and proportion of immature dendritic spines. Conditional loss of Ophn1 function in the mouse model confirmed the immaturity defect and showed that Ophn1 is required at all stages of development. Khelfaoui et al. (2007) conclude that depending on the context, OPHN1 controls the maturation of dendritic spines either by maintaining the density of mature spines or by limiting the extension of new filopodia.
In an affected male from a family with Billuart-type X-linked syndromic intellectual developmental disorder (MRXSBL; 300486), originally designated MRX60, Billuart et al. (1998) detected a 1-bp deletion (1578del) within the valine-526 codon in the OPHN1 gene. RT-PCR analysis using RNA isolated from a lymphoblastoid cell line from the proband showed that the mutation resulted in a barely detectable amount of the oligophrenin-1 transcript. Cosegregation of this frameshift mutation with the disease was confirmed in the large family. The frameshift mutation was not detected in 100 control individuals.
In 4 affected males of a family with Billuart-type X-linked syndromic intellectual developmental disorder (MRXSBL; 300486), Philip et al. (2003) identified an 8-bp duplication in exon 9 of the OPHN1 gene, resulting in a frameshift and premature stop codon.
In a patient with Billuart-type X-linked syndromic intellectual developmental disorder (MRXSBL; 300486), Philip et al. (2003) identified a C-to-T transition in exon 3 of the OPHN1 gene, resulting in a gln62-to-ter (Q62X) substitution.
In 5 affected members of a family with Billuart-type X-linked syndromic intellectual developmental disorder (MRXSBL; 300486), Bergmann et al. (2003) identified a 17.6-kb deletion in the OPHN1 gene, resulting in the deletion of exon 19. The deletion was Alu repeat-mediated.
In 2 affected males from a family with Billuart-type X-linked syndromic intellectual developmental disorder (MRXSBL; 300486), Chabrol et al. (2005) identified a 2-bp deletion in the OPHN1 gene, resulting in a premature stop codon and a truncated protein of 248 amino acids.
In 5 affected sibs of a Saudi family with Billuart-type X-linked syndromic intellectual developmental disorder (MRXSBL; 300486), Al-Owain et al. (2011) identified a 68-kb intragenic deletion spanning exons 7 to 15 and including nearly half of intron 15 of the OPHN1 gene. CGH microarray analysis indicated that the proximal breakpoint was between probes A_16_P21485801 and A_16_P21485807, whereas the distal breakpoint was between probes A_16_P21485905 and A_16_P41692685. There were 4 affected boys and 1 affected girl, who was shown to have random X-chromosome inactivation.
Al-Owain, M., Kaya, N., Al-Zaidan, H., Al-Hashmi, N., Al-Bakheet, A., Al-Muhaizea, M., Chedrawi, A., Basran, R. K., Milunsky, A. Novel intragenic deletion in OPHN1 in a family causing XLMR with cerebellar hypoplasia and distinctive facial appearance. Clin. Genet. 79: 363-370, 2011. [PubMed: 20528889] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01462.x]
Bedeschi, M. F., Novelli, A., Bernardini, L., Parazzini, C., Bianchi, V., Torres, B., Natacci, F., Giuffrida, M. G., Ficarazzi, P., Dallapiccola, B., Lalatta, F. Association of syndromic mental retardation with an Xq12q13.1 duplication encompassing the oligophrenin 1 gene. Am. J. Med. Genet. 146A: 1718-1724, 2008. [PubMed: 18512229] [Full Text: https://doi.org/10.1002/ajmg.a.32365]
Bergmann, C., Zerres, K., Senderek, J., Rudnik-Schoneborn, S., Eggermann, T., Hausler, M., Mull, M., Ramaekers, V. T. Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. Brain 126: 1537-1544, 2003. [PubMed: 12805098] [Full Text: https://doi.org/10.1093/brain/awg173]
Bienvenu, T., Der-Sarkissian, H., Billuart, P., Tissot, M., Des Portes, V., Bruls, T., Chabrolle, J. P., Chauveau, P., Cherry, M., Kahn, A., Cohen, D., Beldjord, C., Chelly, J., Cherif, D. Mapping of the X-breakpoint involved in a balanced X;12 translocation in a female with mild mental retardation. Europ. J. Hum. Genet. 5: 105-109, 1997. [PubMed: 9195162]
Billuart, P., Bienvenu, T., Ronce, N., des Portes, V., Vinet, M. C., Zemni, R., Crollius, H. R., Carrie, A., Fauchereau, F., Cherry, M., Briault, S., Hamel, B., Fryns, J.-P., Beldjord, C., Kahn, A., Moraine, C., Chelly, J. Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation. Nature 392: 923-926, 1998. [PubMed: 9582072] [Full Text: https://doi.org/10.1038/31940]
Chabrol, B., Girard, N., N'Guyen, K., Gerard, A., Carlier, M., Villard, L., Philip, N. Delineation of the clinical phenotype associated with OPHN1 mutations based on the clinical and neuropsychological evaluation of three families. Am. J. Med. Genet. 138A: 314-317, 2005. [PubMed: 16158428] [Full Text: https://doi.org/10.1002/ajmg.a.30882]
Govek, E.-E., Newey, S. E., Akerman, C. J., Cross, J. R., Van der Veken, L., Van Aelst, L. The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. Nature Neurosci. 7: 364-372, 2004. [PubMed: 15034583] [Full Text: https://doi.org/10.1038/nn1210]
Kasri, N. N., Nakano-Kobayashi, A., Malinow, R., Li, B., Van Aelst, L. The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors. Genes Dev. 23: 1289-1302, 2009. [PubMed: 19487570] [Full Text: https://doi.org/10.1101/gad.1783809]
Khelfaoui, M., Denis, C., van Galen, E., de Bock, F., Schmitt, A., Houbron, C., Morice, E., Giros, B., Ramakers, G., Fagni, L., Chelly, J., Nosten-Bernard, M., Billuart, P. Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity. J. Neurosci. 27: 9439-9450, 2007. [PubMed: 17728457] [Full Text: https://doi.org/10.1523/JNEUROSCI.2029-07.2007]
Khelfaoui, M., Pavlowsky, A., Powell, A. D., Valnegri, P., Cheong, K. W., Blandin, Y., Passafaro, M., Jefferys, J. G. R., Chelly, J., Billuart, P. Inhibition of RhoA pathway rescues the endocytosis defects in oligophrenin1 mouse model of mental retardation. Hum. Molec. Genet. 18: 2575-2583, 2009. [PubMed: 19401298] [Full Text: https://doi.org/10.1093/hmg/ddp189]
Philip, N., Chabrol, B., Lossi, A.-M., Cardoso, C., Guerrini, R., Dobyns, W. B., Raybaud, C., Villard, L. Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia. (Letter) J. Med. Genet. 40: 441-446, 2003. [PubMed: 12807966] [Full Text: https://doi.org/10.1136/jmg.40.6.441]
Tentler, D., Gustavsson, P., Leisti, J., Schueler, M., Chelly, J., Timonen, E., Anneren, G., Willard, H. F., Dahl, N. Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia. Europ. J. Hum. Genet. 7: 541-548, 1999. [PubMed: 10439959] [Full Text: https://doi.org/10.1038/sj.ejhg.5200320]
Zanni, G., Saillour, Y., Nagara, M., Billuart, P., Castelnau, L., Moraine, C., Faivre, L., Bertini, E., Durr, A., Guichet, A., Rodriguez, D., des Portes, V., Beldjord, C., Chelly, J. Oligophrenin 1 mutations frequently cause X-linked mental retardation with cerebellar hypoplasia. Neurology 65: 1364-1369, 2005. [PubMed: 16221952] [Full Text: https://doi.org/10.1212/01.wnl.0000182813.94713.ee]