- Email: [email protected]
Genetic study of NRXN1β variants in Spanish patients with schizophrenia
Schizophrenia Research 159 (2014) 554–555
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Genetic study of NRXN1β variants in Spanish patients with schizophrenia
Dear Editors, Schizophrenia is a severe mental disorder with a worldwide prevalence of 1%. Considered a neurodevelopmental disease, its etiology includes a strong genetic component, with heritability estimates of up to 80%. Genetic overlap between schizophrenia and other neurodevelopmental disorders, including attention deficit hyperactivity disorder, intellectual disability and autism, has been reported (Carroll and Owen, 2009). For instance, neurexins and neuroligins are synaptic cell adhesion molecules whose genes have been linked to several neurodevelopmental disorders (Südhof, 2008). The neurexin gene family consists of three members in vertebrates, NRXN1, NRXN2, and NRXN3. Each neurexin gene encodes two isoforms: NRXN-α and NRXN-β. Neurexin-α isoforms are transcribed from a promoter upstream of exon 1, while neurexin-β isoforms are generated from an internal promoter that drives transcription from a β-specific exon (Fig. 1). Point mutations and copy number variants in the NRXN1 gene have been identified in autism (Camacho-Garcia et al., 2012) and schizophrenia (Kirov et al., 2008; Rujescu et al., 2009). We recently reported four novel independent NRXN1-β mutations in Spanish patients with autism and intellectual disability. Mutations c.−3GNT, within the Kozak sequence, and c.3GNT (p.Met1) at the initiation codon, affect positions involved in the initiation of protein translation and are specific to the NRXN1-β isoform (Fig. 1). Mutations p.Arg375Gln and p.Gly378Ser are located within the juxtamembrane region of the extracellular domain and are common to NRXN1-α and -β isoforms (Fig. 1) (Camacho-Garcia et al., 2012). Interestingly, these mutations were found in one patient each (out of 86 studied) and in none of the 200 control individuals and segregate in families with different psychiatric disorders, including schizophrenia (Camacho-Garcia et al., 2012). Given the hypothesis of an overlap in the genetic background of schizophrenia, autism, and intellectual disability, we examined whether the identified mutations were also associated with schizophrenia in a Spanish population. Accordingly, we conducted a case–control study with 445 schizophrenia patients and 615 control subjects from the same Spanish region, with similar genetic background (Roig et al., 2007) and comparable to the original sample were NRXN1-β mutations were identified. Each participating patient met the DSM-IV criteria for the diagnosis of schizophrenia. Controls were selected from a population-based sample and screened for psychiatric disease using the Goldberg Questionnaire (Martorell et al., 2008). The study was carried out with the approval of the Hospital Ethics Committee, and all subjects provided written informed consent. Four specific Custom Taqman Genotyping assays were designed for genotyping: c.−3GN T, c.+3GN T, p.Arg375Gln and p.Gly378Ser (Applied Biosystems, Madrid, Spain). Mutations were
http://dx.doi.org/10.1016/j.schres.2014.09.002 0920-9964/© 2014 Elsevier B.V. All rights reserved.
assessed using a discrimination allele method on an ABI PRISM 7900HT Fast Real-Time PCR System (Applied Biosystems, Madrid, Spain). As a template, we used 20 ng of genomic DNA. The SDS version 2.4 software application (Applied Biosystems Madrid, Spain) was used to automatically assign the allele calls. DNA samples presenting the mutated alleles were used as positive controls in each one of the sample plates. None of the four mutations was identified in the schizophrenia or control groups. Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility to autism, schizophrenia, developmental delay, and dysmorphic features (Béna et al., 2013; Dabell et al., 2013; Schaaf et al., 2012). There is evidence that these disorders have a high concordance in their etiology and pathogenesis, indicating that disruption of neurexin function might predispose to a wide range of neurodevelopmental disorders. However, the majority of NRXN1 deletions in schizophrenia affect the promoter and initial exons of NRXN1-α, while leaving NRXN1β unaltered (Reichelt et al., 2012; Dabell et al., 2013), suggesting that NRXN1-β deletions produce a more severe phenotype or tend towards lethality. The NRXN1-β variants examined in this work were originally identified in patients meeting the diagnostic criteria for autism with intellectual disability. We did not find any of the four studied mutations in either the schizophrenia patient group or the control group, despite the expected genetic overlap among autism, intellectual disability and schizophrenia. It is worth mentioning that we reported a novel, independent mutation affecting the translation initiation site of NRXN1-β in a Spanish patient with high-functioning autism (Camacho-Garcia et al., 2013). Although further studies are needed to establish the involvement of NRXN1-β in schizophrenia, a differential role for mutations in NRXN1-β in autism and schizophrenia might be suggested. Role of the funding source Neither institution had played a role in the study design; in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Contributors NA, BR and LM genotyped all samples. R M-L, FA and CO recruited patients, RJCG, FGS, AMM prepared all four mutation tests, EV and BR designed the project. NA prepared the manuscript draft. All authors disused and edited the manuscript final version. Conflict of interest Authors declare no conflict of interest. Acknowledgments We gratefully acknowledge financial support from our institutions.
References Béna, F., Bruno, D.L., Eriksson, M., van Ravenswaaij-Arts, C., Stark, Z., Dijkhuizen, T., Gerkes, E., Gimelli, S., Ganesamoorthy, D., Thuresson, A.C., Labalme, A., Till, M., Bilan, F., Pasquier, L., Kitzis, A., Dubourgm, C., Rossi, M., Bottani, A., Gagnebin, M., Sanlaville, D., Gilbert-Dussardier, B., Guipponi, M., van Haeringen, A., Kriek, M., Ruivenkamp, C., Antonarakis, S.E., Anderlid, B.M., Slater, H.R., Schoumans, J., 2013. Molecular and clinical characterization of 25 individuals with exonic deletions of
Letter to the Editor
555
Fig. 1. Schematic drawing of human NRXN1 gene showing the position in NRXN1-β of the four mutations studied and the position of NRXN1-α and NRXN1-β isoform promoters. NRXN1 and comprehensive review of the literature. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162, 388–403. http://dx.doi.org/10.1002/ajmg.b.32148. Camacho-Garcia, R.J., Planelles, M.I., Margalef, M., Pecero, M.L., Martínez-Leal, R., Aguilera, F., Vilella, E., Martinez-Mir, A., Scholl, F.G., 2012. Mutations affecting synaptic levels of neurexin-1β in autism and mental retardation. Neurobiol. Dis. 47, 135–143. http://dx. doi.org/10.1016/j.nbd.2012.03.031. Camacho-Garcia, R.J., Hervas, A., Toma, C., Balmana, N., Cormand, B., Martinez-Mir, A., Scholl, F.G., 2013. Rare variants analysis of neurexin-1 beta in autism reveals a novel start codon mutation affecting protein levels at synapses. Psychiatr. Genet. 23, 262–266. http://dx.doi.org/10.1097/Ypg.0000000000000013. Carroll, L.S., Owen, M.J., 2009. Genetic overlap between autism, schizophrenia and bipolar disorder. Genome Med. 1, 102. http://dx.doi.org/10.1186/gm102. Dabell, M.P., Rosenfeld, J. a, Bader, P., Escobar, L.F., El-Khechen, D., Vallee, S.E., Dinulos, M. B.P., Curry, C., Fisher, J., Tervo, R., Hannibal, M.C., Siefkas, K., Wyatt, P.R., Hughes, L., Smith, R., Ellingwood, S., Lacassie, Y., Stroud, T., Farrell, S. a, Sanchez-Lara, P. a, Randolph, L.M., Niyazov, D., Stevens, C. a, Schoonveld, C., Skidmore, D., MacKay, S., Miles, J.H., Moodley, M., Huillet, A., Neill, N.J., Ellison, J.W., Ballif, B.C., Shaffer, L.G., 2013. Investigation of NRXN1 deletions: clinical and molecular characterization. Am. J. Med. Genet. A 161, 717–731. http://dx.doi.org/10.1002/ajmg.a.35780. Kirov, G., Gumus, D., Chen, W., Norton, N., Georgieva, L., Sari, M., O’Donovan, M.C., Erdogan, F., Owen, M.J., Ropers, H.-H., Ullmann, R., 2008. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum. Mol. Genet. 17, 458–465. http://dx.doi.org/10.1093/hmg/ddm323. Martorell, L., Costas, J., Valero, J., Gutierrez-Zotes, A., Phillips, C., Torres, M., Brunet, A., Garrido, G., Carracedo, A., Guillamat, R., Vallès, V., Guitart, M., Labad, A., Vilella, E., 2008. Analyses of variants located in estrogen metabolism genes (ESR1, ESR2, COMT and APOE) and schizophrenia. Schizophr. Res. 100, 308–315. http://dx.doi. org/10.1016/j.schres.2007.11.001. Reichelt, A.C., Rodgers, R.J., Clapcote, S.J., 2012. The role of neurexins in schizophrenia and autistic spectrum disorder. Neuropharmacology http://dx.doi.org/10.1016/j. neuropharm.2011.01.024. Roig, B., Virgos, C., Franco, N., Martorell, L., Valero, J., Costas, J., Carracedo, A., Labad, A., Vilella, E., 2007. The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia. Mol. Psychiatry 12, 833–841. http://dx.doi.org/10.1038/sj.mp. 4001995. Rujescu, D., Ingason, A., Cichon, S., Pietiläinen, O.P.H., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A., Olason, P.I., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Möller, H.-J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A., Franke, B., Veltman, J., Buizer-Voskamp, J.E., Sabatti, C., Ophoff, R.A., Rietschel, M., Nöthen, M.M., Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., Collier, D.A., 2009. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18, 988–996. http://dx.doi.org/10. 1093/hmg/ddn351. Schaaf, C.P., Boone, P.M., Sampath, S., Williams, C., Bader, P.I., Mueller, J.M., Shchelochkov, O.A., Brown, C.W., Crawford, H.P., Phalen, J.A., Tartaglia, N.R., Evans, P., Campbell, W. M., Chun-Hui Tsai, A., Parsley, L., Grayson, S.W., Scheuerle, A., Luzzi, C.D., Thomas, S. K., Eng, P.A., Kang, S.-H.L., Patel, A., Stankiewicz, P., Cheung, S.W., 2012. Phenotypic spectrum and genotype–phenotype correlations of NRXN1 exon deletions. Eur. J. Hum. Genet. http://dx.doi.org/10.1038/ejhg.2012.95. Südhof, T.C., 2008. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911. http://dx.doi.org/10.1038/nature07456.
Nerea Abasolo Bàrbara Roig Lourdes Martorell Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, CIBERSAM, Reus, Spain
Rafael Martínez-Leal Francisco Aguilera Fundació Villablanca, IISPV, Universitat Rovira i Virgili, CIBERSAM, Reus, Spain Rafael Jesús Camacho-García Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain Carmen Orejuela Fundació Villablanca, IISPV, Universitat Rovira i Virgili, CIBERSAM, Reus, Spain Francisco G. Scholl Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain Facultad de Medicina, Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Sevilla, Spain Amalia Martinez-Mir Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain Elisabet Vilella Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, CIBERSAM, Reus, Spain Corresponding author at: Hospital Universitari Institut Pere Mata, Ctra. de l'Institut Pere Mata, s/n, 43206 Reus, Spain. Tel.: +34 977 33 85 65; fax: +34 977 31 00 21. E-mail address: [email protected]. 6 June 2014
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Genetic study of NRXN1β variants in Spanish patients with schizophrenia
Dear Editors, Schizophrenia is a severe mental disorder with a worldwide prevalence of 1%. Considered a neurodevelopmental disease, its etiology includes a strong genetic component, with heritability estimates of up to 80%. Genetic overlap between schizophrenia and other neurodevelopmental disorders, including attention deficit hyperactivity disorder, intellectual disability and autism, has been reported (Carroll and Owen, 2009). For instance, neurexins and neuroligins are synaptic cell adhesion molecules whose genes have been linked to several neurodevelopmental disorders (Südhof, 2008). The neurexin gene family consists of three members in vertebrates, NRXN1, NRXN2, and NRXN3. Each neurexin gene encodes two isoforms: NRXN-α and NRXN-β. Neurexin-α isoforms are transcribed from a promoter upstream of exon 1, while neurexin-β isoforms are generated from an internal promoter that drives transcription from a β-specific exon (Fig. 1). Point mutations and copy number variants in the NRXN1 gene have been identified in autism (Camacho-Garcia et al., 2012) and schizophrenia (Kirov et al., 2008; Rujescu et al., 2009). We recently reported four novel independent NRXN1-β mutations in Spanish patients with autism and intellectual disability. Mutations c.−3GNT, within the Kozak sequence, and c.3GNT (p.Met1) at the initiation codon, affect positions involved in the initiation of protein translation and are specific to the NRXN1-β isoform (Fig. 1). Mutations p.Arg375Gln and p.Gly378Ser are located within the juxtamembrane region of the extracellular domain and are common to NRXN1-α and -β isoforms (Fig. 1) (Camacho-Garcia et al., 2012). Interestingly, these mutations were found in one patient each (out of 86 studied) and in none of the 200 control individuals and segregate in families with different psychiatric disorders, including schizophrenia (Camacho-Garcia et al., 2012). Given the hypothesis of an overlap in the genetic background of schizophrenia, autism, and intellectual disability, we examined whether the identified mutations were also associated with schizophrenia in a Spanish population. Accordingly, we conducted a case–control study with 445 schizophrenia patients and 615 control subjects from the same Spanish region, with similar genetic background (Roig et al., 2007) and comparable to the original sample were NRXN1-β mutations were identified. Each participating patient met the DSM-IV criteria for the diagnosis of schizophrenia. Controls were selected from a population-based sample and screened for psychiatric disease using the Goldberg Questionnaire (Martorell et al., 2008). The study was carried out with the approval of the Hospital Ethics Committee, and all subjects provided written informed consent. Four specific Custom Taqman Genotyping assays were designed for genotyping: c.−3GN T, c.+3GN T, p.Arg375Gln and p.Gly378Ser (Applied Biosystems, Madrid, Spain). Mutations were
http://dx.doi.org/10.1016/j.schres.2014.09.002 0920-9964/© 2014 Elsevier B.V. All rights reserved.
assessed using a discrimination allele method on an ABI PRISM 7900HT Fast Real-Time PCR System (Applied Biosystems, Madrid, Spain). As a template, we used 20 ng of genomic DNA. The SDS version 2.4 software application (Applied Biosystems Madrid, Spain) was used to automatically assign the allele calls. DNA samples presenting the mutated alleles were used as positive controls in each one of the sample plates. None of the four mutations was identified in the schizophrenia or control groups. Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility to autism, schizophrenia, developmental delay, and dysmorphic features (Béna et al., 2013; Dabell et al., 2013; Schaaf et al., 2012). There is evidence that these disorders have a high concordance in their etiology and pathogenesis, indicating that disruption of neurexin function might predispose to a wide range of neurodevelopmental disorders. However, the majority of NRXN1 deletions in schizophrenia affect the promoter and initial exons of NRXN1-α, while leaving NRXN1β unaltered (Reichelt et al., 2012; Dabell et al., 2013), suggesting that NRXN1-β deletions produce a more severe phenotype or tend towards lethality. The NRXN1-β variants examined in this work were originally identified in patients meeting the diagnostic criteria for autism with intellectual disability. We did not find any of the four studied mutations in either the schizophrenia patient group or the control group, despite the expected genetic overlap among autism, intellectual disability and schizophrenia. It is worth mentioning that we reported a novel, independent mutation affecting the translation initiation site of NRXN1-β in a Spanish patient with high-functioning autism (Camacho-Garcia et al., 2013). Although further studies are needed to establish the involvement of NRXN1-β in schizophrenia, a differential role for mutations in NRXN1-β in autism and schizophrenia might be suggested. Role of the funding source Neither institution had played a role in the study design; in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Contributors NA, BR and LM genotyped all samples. R M-L, FA and CO recruited patients, RJCG, FGS, AMM prepared all four mutation tests, EV and BR designed the project. NA prepared the manuscript draft. All authors disused and edited the manuscript final version. Conflict of interest Authors declare no conflict of interest. Acknowledgments We gratefully acknowledge financial support from our institutions.
References Béna, F., Bruno, D.L., Eriksson, M., van Ravenswaaij-Arts, C., Stark, Z., Dijkhuizen, T., Gerkes, E., Gimelli, S., Ganesamoorthy, D., Thuresson, A.C., Labalme, A., Till, M., Bilan, F., Pasquier, L., Kitzis, A., Dubourgm, C., Rossi, M., Bottani, A., Gagnebin, M., Sanlaville, D., Gilbert-Dussardier, B., Guipponi, M., van Haeringen, A., Kriek, M., Ruivenkamp, C., Antonarakis, S.E., Anderlid, B.M., Slater, H.R., Schoumans, J., 2013. Molecular and clinical characterization of 25 individuals with exonic deletions of
Letter to the Editor
555
Fig. 1. Schematic drawing of human NRXN1 gene showing the position in NRXN1-β of the four mutations studied and the position of NRXN1-α and NRXN1-β isoform promoters. NRXN1 and comprehensive review of the literature. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162, 388–403. http://dx.doi.org/10.1002/ajmg.b.32148. Camacho-Garcia, R.J., Planelles, M.I., Margalef, M., Pecero, M.L., Martínez-Leal, R., Aguilera, F., Vilella, E., Martinez-Mir, A., Scholl, F.G., 2012. Mutations affecting synaptic levels of neurexin-1β in autism and mental retardation. Neurobiol. Dis. 47, 135–143. http://dx. doi.org/10.1016/j.nbd.2012.03.031. Camacho-Garcia, R.J., Hervas, A., Toma, C., Balmana, N., Cormand, B., Martinez-Mir, A., Scholl, F.G., 2013. Rare variants analysis of neurexin-1 beta in autism reveals a novel start codon mutation affecting protein levels at synapses. Psychiatr. Genet. 23, 262–266. http://dx.doi.org/10.1097/Ypg.0000000000000013. Carroll, L.S., Owen, M.J., 2009. Genetic overlap between autism, schizophrenia and bipolar disorder. Genome Med. 1, 102. http://dx.doi.org/10.1186/gm102. Dabell, M.P., Rosenfeld, J. a, Bader, P., Escobar, L.F., El-Khechen, D., Vallee, S.E., Dinulos, M. B.P., Curry, C., Fisher, J., Tervo, R., Hannibal, M.C., Siefkas, K., Wyatt, P.R., Hughes, L., Smith, R., Ellingwood, S., Lacassie, Y., Stroud, T., Farrell, S. a, Sanchez-Lara, P. a, Randolph, L.M., Niyazov, D., Stevens, C. a, Schoonveld, C., Skidmore, D., MacKay, S., Miles, J.H., Moodley, M., Huillet, A., Neill, N.J., Ellison, J.W., Ballif, B.C., Shaffer, L.G., 2013. Investigation of NRXN1 deletions: clinical and molecular characterization. Am. J. Med. Genet. A 161, 717–731. http://dx.doi.org/10.1002/ajmg.a.35780. Kirov, G., Gumus, D., Chen, W., Norton, N., Georgieva, L., Sari, M., O’Donovan, M.C., Erdogan, F., Owen, M.J., Ropers, H.-H., Ullmann, R., 2008. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum. Mol. Genet. 17, 458–465. http://dx.doi.org/10.1093/hmg/ddm323. Martorell, L., Costas, J., Valero, J., Gutierrez-Zotes, A., Phillips, C., Torres, M., Brunet, A., Garrido, G., Carracedo, A., Guillamat, R., Vallès, V., Guitart, M., Labad, A., Vilella, E., 2008. Analyses of variants located in estrogen metabolism genes (ESR1, ESR2, COMT and APOE) and schizophrenia. Schizophr. Res. 100, 308–315. http://dx.doi. org/10.1016/j.schres.2007.11.001. Reichelt, A.C., Rodgers, R.J., Clapcote, S.J., 2012. The role of neurexins in schizophrenia and autistic spectrum disorder. Neuropharmacology http://dx.doi.org/10.1016/j. neuropharm.2011.01.024. Roig, B., Virgos, C., Franco, N., Martorell, L., Valero, J., Costas, J., Carracedo, A., Labad, A., Vilella, E., 2007. The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia. Mol. Psychiatry 12, 833–841. http://dx.doi.org/10.1038/sj.mp. 4001995. Rujescu, D., Ingason, A., Cichon, S., Pietiläinen, O.P.H., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A., Olason, P.I., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Möller, H.-J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A., Franke, B., Veltman, J., Buizer-Voskamp, J.E., Sabatti, C., Ophoff, R.A., Rietschel, M., Nöthen, M.M., Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., Collier, D.A., 2009. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18, 988–996. http://dx.doi.org/10. 1093/hmg/ddn351. Schaaf, C.P., Boone, P.M., Sampath, S., Williams, C., Bader, P.I., Mueller, J.M., Shchelochkov, O.A., Brown, C.W., Crawford, H.P., Phalen, J.A., Tartaglia, N.R., Evans, P., Campbell, W. M., Chun-Hui Tsai, A., Parsley, L., Grayson, S.W., Scheuerle, A., Luzzi, C.D., Thomas, S. K., Eng, P.A., Kang, S.-H.L., Patel, A., Stankiewicz, P., Cheung, S.W., 2012. Phenotypic spectrum and genotype–phenotype correlations of NRXN1 exon deletions. Eur. J. Hum. Genet. http://dx.doi.org/10.1038/ejhg.2012.95. Südhof, T.C., 2008. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911. http://dx.doi.org/10.1038/nature07456.
Nerea Abasolo Bàrbara Roig Lourdes Martorell Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, CIBERSAM, Reus, Spain
Rafael Martínez-Leal Francisco Aguilera Fundació Villablanca, IISPV, Universitat Rovira i Virgili, CIBERSAM, Reus, Spain Rafael Jesús Camacho-García Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain Carmen Orejuela Fundació Villablanca, IISPV, Universitat Rovira i Virgili, CIBERSAM, Reus, Spain Francisco G. Scholl Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain Facultad de Medicina, Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Sevilla, Spain Amalia Martinez-Mir Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain Elisabet Vilella Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, CIBERSAM, Reus, Spain Corresponding author at: Hospital Universitari Institut Pere Mata, Ctra. de l'Institut Pere Mata, s/n, 43206 Reus, Spain. Tel.: +34 977 33 85 65; fax: +34 977 31 00 21. E-mail address: [email protected]. 6 June 2014