Alternative titles; symbols
HGNC Approved Gene Symbol: SRPX2
Cytogenetic location: Xq22.1 Genomic coordinates (GRCh38) : X:100,644,199-100,675,788 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq22.1 | ?Rolandic epilepsy, impaired intellectual development, and speech dyspraxia | 300643 | 3 |
The E2A/HLF fusion gene (see 147141) is generated by t(17;19)(q23;p13) translocations in cases of pro-B acute leukemia. Using representational difference analysis to identify genes upregulated by the E2A/HLF fusion protein, followed by screening heart and pro-B-cell cDNA libraries, Kurosawa et al. (1999) cloned SRPX2, which they called SRPUL. The deduced 465-amino acid protein has a calculated molecular mass of 53 kD. It has an N-terminal signal peptide and 3 consensus sushi repeats, each of which spans approximately 60 amino acids and contains 6 conserved cysteines. SRPUL shares 47% amino acid identity with SRPX (300187). Northern blot analysis detected highest expression of a 2.5-kb SRPUL transcript in heart, ovary, and placenta, with little to no expression in other tissues examined. In vitro translated SRPUL had an apparent molecular mass of 50 kD. Immunofluorescence analysis of transfected mouse pro-B lymphocytic cells showed a cytoplasmic distribution. SRPUL was secreted into the medium of mouse pro-B cells.
By in situ hybridization, Western blot, and immunohistochemical analyses, Salmi et al. (2013) found that Srpx2 mRNA and protein were expressed in embryonic rat brain during various developmental stages. Srpx2 was expressed from the proliferative ventricular/subventricular zones to the cortical place, predominantly in neural and neuronal progenitor cells and along radial glial processes.
Kurosawa et al. (1999) found that E2A/HLF upregulated expression of SRPUL and annexin-8 (ANXA8; 602396) in pro-B cells. Transfection of a human myeloid leukemia cell line with E2A/HLF induced expression of ANXA8, but not SRPUL. E2A/HLF protected mouse pro-B cells from apoptosis caused by IL3 (147740) deprivation, but neither ANXA8 or SRPUL could block apoptosis.
By yeast 2-hybrid analysis of a human brain cDNA library, Royer-Zemmour et al. (2008) showed that SRPX2 interacted with urokinase-type plasminogen activator receptor (UPAR, or PLAUR; 173391), cathepsin B (CTSB; 116810), and aggrecanase-1 (ADAMTS4; 603876), all of which are involved in extracellular proteolysis. Coimmunoprecipitation analysis confirmed these interactions. RT-PCR detected coexpression of SRPX2 and UPAR in human temporal cortex, including the rolandic area, and in rat brain at all developmental stages analyzed. SRPX2 bound human UPAR expressed on the surface of transfected COS cells, indicating that SRPX2 bound the extracellular portion of UPAR. Mutation analysis showed that SRPX2 interacted with both the D1 and D2-D3 extracellular domains of UPAR.
Using gel retardation, quantitative RT-PCR, and reporter gene assays, Roll et al. (2010) found that human FOXP2 (605317) bound the promoter regions of SRPX2 and UPAR and downregulated their expression. Foxp2-binding sites were conserved in the promoter regions of chimpanzee and mouse Srpx2 and in chimpanzee Upar, but Foxp2-binding sites were not conserved in mouse Upar.
Using microarray analysis and quantitative real-time PCR, Schwanzer-Pfeiffer et al. (2010) found that expression of SVEP1 (611691), SRPX2, and KIAA0247 (SUSD6; 616761) was significantly upregulated in a human cell culture model of endotoxemia. Knockdown of SRPX2 via small interfering RNA reduced expression of ICAM1 (147840) and E-selectin (SELE; 131210) on the surface of stimulated human umbilical vein endothelial cells (HUVECs) and increased soluble ICAM1 and E-selectin concentrations in supernatant.
Sia et al. (2013) showed that the SRPX2 gene encodes a protein that promotes synaptogenesis in the cerebral cortex. In humans, SRPX2 is an epilepsy- and language-associated gene that is a target of the FOXP2 transcription factor. Sia et al. (2013) showed that FOXP2 modulates synapse formation through regulating SRPX2 levels and that SRPX2 reduction impairs development of ultrasonic vocalization in mice. The results of Sia et al. (2013) suggested that FOXP2 modulates the development of neural circuits through regulating synaptogenesis and that SRPX2 is a synaptogenic factor that plays a role in the pathogenesis of language disorders.
Salmi et al. (2013) found that Chinese hamster ovary cells cultured in medium containing rat or human SRPX2 increased acetylation of alpha-tubulin (see 602529). This effect was independent of Upar.
Roll et al. (2006) identified the SRPX2 gene on the X chromosome within a 21-cM region between markers {dbSNP ss16361056} and DXS1230 identified by linkage analysis in a family with X-linked rolandic epilepsy with speech dyspraxia (RESDX; 300643).
The rolandic and sylvian fissures divide the human cerebral hemispheres, and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known. Roll et al. (2006) identified mutations in SRPX2 as being responsible for X-linked rolandic seizures associated with oral and speech dyspraxia and impaired intellectual development (RESDX; 300643). One potential disease-causing variant (N327S; 300642.0001), which was identified in affected members of a French family, resulted in gain of glycosylation of the secreted mutant protein. A second mutation (Y72S; 300642.0002) was identified within the first sushi domain of SRPX2 in a boy with rolandic seizures and in his female relatives with mildly impaired intellectual development or unaffected carrier status. The boy also had MRI evidence of bilateral perisylvian polymicrogyria (300388). In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The authors suggested that SRPX2 may play an important role in the development and/or function of the perisylvian region critical for language and cognitive development.
Reclassified Variants
The N327S variant (300643.0001) identified by Roll et al. (2006) in patients with rolandic epilepsy has been reclassified as a variant of unknown significance.
Reinthaler et al. (2014) found the N327S variant (rs121918363) in 2 (0.81%) of 247 patients with rolandic epilepsy who underwent direct sequencing of the SRPX2 gene and in 12 (0.26%) of 4,703 European controls, including those from the Exome Variant Server database. Sequence variants and structural variation were not found in the SRPX2 gene or in 4 interaction partners. Reinthaler et al. (2014) concluded that variation in the SRPX2 gene does not play a major role, if any, in rolandic epilepsy.
Salmi et al. (2013) found that silencing rat Srpx2 expression in utero at embryonic day 15 altered the position of projection neurons in the cerebral cortex, altered the orientation of apical dendrites, reduced dendritic length and number, and increased postnatal susceptibility to chemical-induced seizures. Neuronal migration defects and postnatal epileptic consequences were prevented by maternal inhibition of the alpha-tubulin deacetylase Hdac6 (300272). Wildtype human SRPX2, but not SRPX2 with the Y72S mutation, rescued the phenotype caused by silencing Srpx2. In contrast, expression of SRPX2 with the N327S mutation in the absence of Srpx2 silencing caused abnormal neuronal migration in rat embryos in a dominant-negative manner.
This variant, formerly titled ROLANDIC EPILEPSY, IMPAIRED INTELLECTUAL DEVELOPMENT, AND SPEECH DYSPRAXIA, X-LINKED, has been reclassified based on the findings of Reinthaler et al. (2014).
In affected members of a 3-generation French family with rolandic epilepsy, speech dyspraxia, and mental retardation (RESDX; 300643), Roll et al. (2006) identified an A-to-G transition at nucleotide 980 in exon 9 of the SRPX2 gene that was predicted to result in substitution of serine for asparagine-327 (N327S). Transfection of the mutation into CHO cells showed that it caused a partial gain of N-glycosylation of the mutant protein and abnormal retention of the mutant protein within the endoplasmic reticulum, consistent with misfolding.
In the family reported by Roll et al. (2006), Lesca et al. (2013) identified a heterozygous ala716-to-thr (A716T) substitution at a highly conserved residue in the GRIN2A gene (138253) that is associated with focal epilepsy and speech disorder with or without mental retardation (FESD; 245570). All but 2 affected family members with the SRPX2 mutation also carried the GRIN2A mutation. All patients with the GRIN2A mutation had seizures, whereas the 2 patients with only the SRPX2 mutation and not the GRIN2A mutation did not have seizures. It was unclear whether the 2 mutations acted synergistically or independently to affect the phenotype in this family.
Salmi et al. (2013) found that expression of mutant N327S in rat embryos caused abnormal neuronal migration in a dominant-negative manner and was associated with postnatal increase in epileptiform activity.
Piton et al. (2013) found the N327S variant in 3 males and 8 females of European descent in the Exome Variant Server database. Based on these findings, as well as a lack of reported SRPX2 mutations since 2006, Piton et al. (2013) classified the involvement of SRPX2 mutations in epilepsy and/or cognitive impairment as questionable.
Reinthaler et al. (2014) found the N327S variant (rs121918363) in 2 (0.81%) of 247 patients with rolandic epilepsy who underwent direct sequencing of the SRPX2 gene and in 12 (0.26%) of 4,703 European controls, including those from the Exome Variant Server database. Sequence variants and structural variation were not found in the SRPX2 gene or in 4 interaction partners. Reinthaler et al. (2014) concluded that variation in the SRPX2 gene does not play a major role, if any, in rolandic epilepsy.
In a 15-year-old male (patient T2472-1) with rolandic seizures, speech dyspraxia, and impaired intellectual development (RESDX; 300643), Roll et al. (2006) identified an A-to-C transversion at nucleotide 215 in exon 4 of the SRPX2 gene that was predicted to result in substitution of serine for the conserved tyrosine-72 (Y72S) in the first sushi domain. The mutation was also found in his unaffected mother and an unaffected aunt, as well as in 2 maternal aunts with mild mental retardation but normal brain MRI studies. Cellular transfection studies indicated that the mutant Y72S protein was partially retained, consistent with misfolding.
Royer-Zemmour et al. (2008) showed that the Y72S mutation increased the apparent binding affinity between SRPX2 and the extracellular domain of UPAR (PLAUR; 173391).
Salmi et al. (2013) found that mutant Y72S failed to rescue the abnormal neuronal migration phenotype of Srpx2-null rats, suggesting that the mutation results in a loss of function.
Kurosawa, H., Goi, K., Inukai, T., Inaba, T., Chang, K.-S., Shinjyo, T., Rakestraw, K. M., Naeve, C. W., Look, A. T. Two candidate downstream target genes for E2A-HLF. Blood 93: 321-332, 1999. [PubMed: 9864177]
Lesca, G., Rudolf, G., Bruneau, N., Lozovaya, N., Labalme, A., Boutry-Kryza, N., Salmi, M., Tsintsadze, T., Addis, L., Motte, J., Wright, S., Tsintsadze, V., and 17 others. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nature Genet. 45: 1061-1066, 2013. [PubMed: 23933820] [Full Text: https://doi.org/10.1038/ng.2726]
Piton, A., Redin, C., Mandel, J.-L. XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am. J. Hum. Genet. 93: 368-383, 2013. Note: Erratum: Am. J. Hum. Genet. 93: 406 only, 2013. [PubMed: 23871722] [Full Text: https://doi.org/10.1016/j.ajhg.2013.06.013]
Reinthaler, E. M., Lal, D., Jurkowski, W., Feucht, M., Steinbock, H., Gruber-Sedlmayr, U., Ronen, G. M., Geldner, J., Haberlandt, E., Neophytou, B., Hahn, A., Altmuller, J., Thiele, H., Toliat, M. R., EuroEPINOMICS Consortium, Lerche, H., Nurnberg, P., Sander, T., Neubauer, B. A., Zimprich, F. Analysis of ELP4, SRPX2, and interacting genes in typical and atypical rolandic epilepsy. Epilepsia 55: e89-e93, 2014. Note: Electronic Article. [PubMed: 24995671] [Full Text: https://doi.org/10.1111/epi.12712]
Roll, P., Rudolf, G., Pereira, S., Royer, B., Scheffer, I. E., Massacrier, A., Valenti, M.-P., Roeckel-Trevisiol, N., Jamali, S., Beclin, C., Seegmuller, C.., Metz-Lutz, M.-N. {and 18 others}: SRPX2 mutations in disorders of language cortex and cognition. Hum. Molec. Genet. 15: 1195-1207, 2006. [PubMed: 16497722] [Full Text: https://doi.org/10.1093/hmg/ddl035]
Roll, P., Vernes, S. C., Bruneau, N., Cillario, J., Ponsole-Lenfant, M., Massacrier, A., Rudolf, G., Khalife, M., Hirsch, E., Fisher, S. E., Szepetowski, P. Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex. Hum. Molec. Genet. 19: 4848-4860, 2010. [PubMed: 20858596] [Full Text: https://doi.org/10.1093/hmg/ddq415]
Royer-Zemmour, B., Ponsole-Lenfant, M., Gara, H., Roll, P., Leveque, C., Massacrier, A., Ferracci, G., Cillario, J., Robaglia-Schlupp, A., Vincentelli, R., Cau, P., Szepetowski, P. Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR. Hum. Molec. Genet. 17: 3617-3630, 2008. [PubMed: 18718938] [Full Text: https://doi.org/10.1093/hmg/ddn256]
Salmi, M., Bruneau, N., Cillario, J., Lozovaya, N., Massacrier, A., Buhler, E., Cloarec, R., Tsintsadze, T., Watrin, F., Tsintsadze, V., Zimmer, C., Villard, C., and 13 others. Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero. Brain 136: 2457-2473, 2013. [PubMed: 23831613] [Full Text: https://doi.org/10.1093/brain/awt161]
Schwanzer-Pfeiffer, D., Rossmanith, E., Schildberger, A., Falkenhagen, D. Characterization of SVEP1, KAA, and SRPX2 in an in vitro cell culture model of endotoxemia. Cell. Immun. 263: 65-70, 2010. [PubMed: 20236627] [Full Text: https://doi.org/10.1016/j.cellimm.2010.02.017]
Sia, G. M., Clem, R. L., Huganir, R. L. The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice. Science 342: 987-991, 2013. [PubMed: 24179158] [Full Text: https://doi.org/10.1126/science.1245079]