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189 results on '"Baldassari S"'

4. WS05.02 CFTR rescue by lumacaftor (VX-809) induces an extensive reorganisation of mitochondria in the cystic fibrosis bronchial epithelium

Author

Armirotti, A., primary, Braccia, C., additional, Christopher, J., additional, Crook, O., additional, Breckels, L., additional, Queiroz, R., additional, Liessi, N., additional, Tomati, V., additional, Capurro, V., additional, Bandiera, T., additional, Baldassari, S., additional, Pedemonte, N., additional, and Lilley, K., additional

Published
2022
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5. Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis

Author

Lee, WS, Baldassari, S, Stephenson, SEM, Lockhart, PJ, Baulac, S, Leventer, RJ, Lee, WS, Baldassari, S, Stephenson, SEM, Lockhart, PJ, Baulac, S, and Leventer, RJ

Abstract

Type II focal cortical dysplasia (FCD) is a neuropathological entity characterised by cortical dyslamination with the presence of dysmorphic neurons only (FCDIIA) or the presence of both dysmorphic neurons and balloon cells (FCDIIB). The year 2021 marks the 50th anniversary of the recognition of FCD as a cause of drug resistant epilepsy, and it is now the most common reason for epilepsy surgery. The causes of FCD remained unknown until relatively recently. The study of resected human FCD tissue using novel genomic technologies has led to remarkable advances in understanding the genetic basis of FCD. Mechanistic parallels have emerged between these non-neoplastic lesions and neoplastic disorders of cell growth and differentiation, especially through perturbations of the mammalian target of rapamycin (mTOR) signalling pathway. This narrative review presents the advances through which the aetiology of FCDII has been elucidated in chronological order, from recognition of an association between FCD and the mTOR pathway to the identification of somatic mosaicism within FCD tissue. We discuss the role of a two-hit mechanism, highlight current challenges and future directions in detecting somatic mosaicism in brain and discuss how knowledge of FCD may inform novel precision treatments of these focal epileptogenic malformations of human cortical development.

Published
2022

8. Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia

Author

Lee, WS, Baldassari, S, Chipaux, M, Adle-Biassette, H, Stephenson, SEM, Maixner, W, Harvey, AS, Lockhart, PJ, Baulac, S, Leventer, RJ, Lee, WS, Baldassari, S, Chipaux, M, Adle-Biassette, H, Stephenson, SEM, Maixner, W, Harvey, AS, Lockhart, PJ, Baulac, S, and Leventer, RJ

Abstract

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are related malformations with shared etiologies. We report three patients with a spectrum of cortical malformations associated with pathogenic brain-specific somatic Ras homolog enriched in brain (RHEB) variants. The somatic variant load directly correlated with the size of the malformation, with upregulated mTOR activity confirmed in dysplastic tissues. Laser capture microdissection showed enrichment of RHEB variants in dysmorphic neurons and balloon cells. Our findings support the role of RHEB in a spectrum of cortical malformations confirming that FCD and HME represent a disease continuum, with the extent of dysplastic brain directly correlated with the somatic variant load.

Published
2021

10. The landscape of epilepsy-related GATOR1 variants (vol 21, pg 398, 2019)

Author

Baldassari, S., Picard, F., Verbeek, N.E., Kempen, M. van, Brilstra, E.H., Lesca, G., Conti, V., Guerrini, R., Bisulli, F., Licchetta, L., Pippucci, T., Tinuper, P., Hirsch, E., Saint Martin, A. de, Chelly, J., Rudolf, G., Chipaux, M., Ferrand-Sorbets, S., Dorfmuller, G., Sisodiya, S., Balestrini, S., Schoeler, N., Hernandez-Hernandez, L., Krithika, S., Oegema, R., Hagebeuk, E., Gunning, B., Deckers, C., Berghuis, B., Wegner, I., Niks, E.H., Jansen, F.E., Braun, K., Jong, D. de, Rubboli, G., Talvik, I., Sander, V., Uldall, P., Jacquemont, M.L., Nava, C., Leguern, E., Julia, S., Gambardella, A., d'Orsi, G., Crichiutti, G., Faivre, L., Darmency, V., Benova, B., Krsek, P., Biraben, A., Lebre, A.S., Jennesson, M., Sattar, S., Marchal, C., Nordli, D.R., Lindstrom, K., Striano, P., Lomax, L.B., Kiss, C., Bartolomei, F., Lepine, A.F., Schoonjans, A.S., Stouffs, K., Jansen, A., Panagiotakaki, E., Ricard-Mousnier, B., Thevenon, J., Bellescize, J. de, Catenoix, H., Dorn, T., Zenker, M., Muller-Schluter, K., Brandt, C., Krey, I., Polster, T., Wolff, M., Balci, M., Rostasy, K., Achaz, G., Zacher, P., Becher, T., Cloppenborg, T., Yuskaitis, C.J., Weckhuysen, S., Poduri, A., Lemke, J.R., Moller, R.S., and Baulac, S.

Published
2019

11. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro, V. Dixon, C.L. Guo, H. Bello, O.D. Vandrovcova, J. Efthymiou, S. Maroofian, R. Heimer, G. Burglen, L. Valence, S. Torti, E. Hacke, M. Rankin, J. Tariq, H. Colin, E. Procaccio, V. Striano, P. Mankad, K. Lieb, A. Chen, S. Pisani, L. Bettencourt, C. Männikkö, R. Manole, A. Brusco, A. Grosso, E. Ferrero, G.B. Armstrong-Moron, J. Gueden, S. Bar-Yosef, O. Tzadok, M. Monaghan, K.G. Santiago-Sim, T. Person, R.E. Cho, M.T. Willaert, R. Yoo, Y. Chae, J.-H. Quan, Y. Wu, H. Wang, T. Bernier, R.A. Xia, K. Blesson, A. Jain, M. Motazacker, M.M. Jaeger, B. Schneider, A.L. Boysen, K. Muir, A.M. Myers, C.T. Gavrilova, R.H. Gunderson, L. Schultz-Rogers, L. Klee, E.W. Dyment, D. Osmond, M. Parellada, M. Llorente, C. Gonzalez-Peñas, J. Carracedo, A. Van Haeringen, A. Ruivenkamp, C. Nava, C. Heron, D. Nardello, R. Iacomino, M. Minetti, C. Skabar, A. Fabretto, A. Hanna, M.G. Bugiardini, E. Hostettler, I. O’Callaghan, B. Khan, A. Cortese, A. O’Connor, E. Yau, W.Y. Bourinaris, T. Kaiyrzhanov, R. Chelban, V. Madej, M. Diana, M.C. Vari, M.S. Pedemonte, M. Bruno, C. Balagura, G. Scala, M. Fiorillo, C. Nobili, L. Malintan, N.T. Zanetti, M.N. Krishnakumar, S.S. Lignani, G. Jepson, J.E.C. Broda, P. Baldassari, S. Rossi, P. Fruscione, F. Madia, F. Traverso, M. De-Marco, P. Pérez-Dueñas, B. Munell, F. Kriouile, Y. El-Khorassani, M. Karashova, B. Avdjieva, D. Kathom, H. Tincheva, R. Van-Maldergem, L. Nachbauer, W. Boesch, S. Gagliano, A. Amadori, E. Goraya, J.S. Sultan, T. Kirmani, S. Ibrahim, S. Jan, F. Mine, J. Banu, S. Veggiotti, P. Zuccotti, G.V. Ferrari, M.D. Van Den Maagdenberg, A.M.J. Verrotti, A. Marseglia, G.L. Savasta, S. Soler, M.A. Scuderi, C. Borgione, E. Chimenz, R. Gitto, E. Dipasquale, V. Sallemi, A. Fusco, M. Cuppari, C. Cutrupi, M.C. Ruggieri, M. Cama, A. Capra, V. Mencacci, N.E. Boles, R. Gupta, N. Kabra, M. Papacostas, S. Zamba-Papanicolaou, E. Dardiotis, E. Maqbool, S. Rana, N. Atawneh, O. Lim, S.Y. Shaikh, F. Koutsis, G. Breza, M. Coviello, D.A. Dauvilliers, Y.A. AlKhawaja, I. AlKhawaja, M. Al-Mutairi, F. Stojkovic, T. Ferrucci, V. Zollo, M. Alkuraya, F.S. Kinali, M. Sherifa, H. Benrhouma, H. Turki, I.B.Y. Tazir, M. Obeid, M. Bakhtadze, S. Saadi, N.W. Zaki, M.S. Triki, C.C. Benfenati, F. Gustincich, S. Kara, M. Belcastro, V. Specchio, N. Capovilla, G. Karimiani, E.G. Salih, A.M. Okubadejo, N.U. Ojo, O.O. Oshinaike, O.O. Oguntunde, O. Wahab, K. Bello, A.H. Abubakar, S. Obiabo, Y. Nwazor, E. Ekenze, O. Williams, U. Iyagba, A. Taiwo, L. Komolafe, M. Senkevich, K. Shashkin, C. Zharkynbekova, N. Koneyev, K. Manizha, G. Isrofilov, M. Guliyeva, U. Salayev, K. Khachatryan, S. Rossi, S. Silvestri, G. Haridy, N. Ramenghi, L.A. Xiromerisiou, G. David, E. Aguennouz, M. Fidani, L. Spanaki, C. Tucci, A. Raspall-Chaure, M. Chez, M. Tsai, A. Fassi, E. Shinawi, M. Constantino, J.N. De Zorzi, R. Fortuna, S. Kok, F. Keren, B. Bonneau, D. Choi, M. Benzeev, B. Zara, F. Mefford, H.C. Scheffer, I.E. Clayton-Smith, J. Macaya, A. Rothman, J.E. Eichler, E.E. Kullmann, D.M. Houlden, H. SYNAPS Study Group

Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. © 2019, The Author(s).

Published
2019

18. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Author

Corbett, MA, Kroes, T, Veneziano, L, Bennett, MF, Florian, R, Schneider, AL, Coppola, A, Licchetta, L, Franceschetti, S, Suppa, A, Wenger, A, Mei, D, Pendziwiat, M, Kaya, S, Delledonne, M, Straussberg, R, Xumerle, L, Regan, B, Crompton, D, van Rootselaar, A-F, Correll, A, Catford, R, Bisulli, F, Chakraborty, S, Baldassari, S, Tinuper, P, Barton, K, Carswell, S, Smith, M, Berardelli, A, Carroll, R, Gardner, A, Friend, KL, Blatt, I, Iacomino, M, Di Bonaventura, C, Striano, S, Buratti, J, Keren, B, Nava, C, Forlani, S, Rudolf, G, Hirsch, E, Leguern, E, Labauge, P, Balestrini, S, Sander, JW, Afawi, Z, Helbig, I, Ishiura, H, Tsuji, S, Sisodiya, SM, Casari, G, Sadleir, LG, van Coller, R, Tijssen, MAJ, Klein, KM, van den Maagdenberg, AMJM, Zara, F, Guerrini, R, Berkovic, SF, Pippucci, T, Canafoglia, L, Bahlo, M, Striano, P, Scheffer, IE, Brancati, F, Depienne, C, Gecz, J, Corbett, MA, Kroes, T, Veneziano, L, Bennett, MF, Florian, R, Schneider, AL, Coppola, A, Licchetta, L, Franceschetti, S, Suppa, A, Wenger, A, Mei, D, Pendziwiat, M, Kaya, S, Delledonne, M, Straussberg, R, Xumerle, L, Regan, B, Crompton, D, van Rootselaar, A-F, Correll, A, Catford, R, Bisulli, F, Chakraborty, S, Baldassari, S, Tinuper, P, Barton, K, Carswell, S, Smith, M, Berardelli, A, Carroll, R, Gardner, A, Friend, KL, Blatt, I, Iacomino, M, Di Bonaventura, C, Striano, S, Buratti, J, Keren, B, Nava, C, Forlani, S, Rudolf, G, Hirsch, E, Leguern, E, Labauge, P, Balestrini, S, Sander, JW, Afawi, Z, Helbig, I, Ishiura, H, Tsuji, S, Sisodiya, SM, Casari, G, Sadleir, LG, van Coller, R, Tijssen, MAJ, Klein, KM, van den Maagdenberg, AMJM, Zara, F, Guerrini, R, Berkovic, SF, Pippucci, T, Canafoglia, L, Bahlo, M, Striano, P, Scheffer, IE, Brancati, F, Depienne, C, and Gecz, J

Abstract

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.

Published
2019

19. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro, V, Dixon, CL, Guo, H, Bello, OD, Vandrovcova, J, Efthymiou, S, Maroofian, R, Heimer, G, Burglen, L, Valence, S, Torti, E, Hacke, M, Rankin, J, Tariq, H, Colin, E, Procaccio, V, Striano, P, Mankad, K, Lieb, A, Chen, S, Pisani, L, Bettencourt, C, Mannikko, R, Manole, A, Brusco, A, Grosso, E, Ferrero, GB, Armstrong-Moron, J, Gueden, S, Bar-Yosef, O, Tzadok, M, Monaghan, KG, Santiago-Sim, T, Person, RE, Cho, MT, Willaert, R, Yoo, Y, Chae, J-H, Quan, Y, Wu, H, Wang, T, Bernier, RA, Xia, K, Blesson, A, Jain, M, Motazacker, MM, Jaeger, B, Schneider, AL, Boysen, K, Muir, AM, Myers, CT, Gavrilova, RH, Gunderson, L, Schultz-Rogers, L, Klee, EW, Dyment, D, Osmond, M, Parellada, M, Llorente, C, Gonzalez-Penas, J, Carracedo, A, Van Haeringen, A, Ruivenkamp, C, Nava, C, Heron, D, Nardello, R, Iacomino, M, Minetti, C, Skabar, A, Fabretto, A, Chez, M, Tsai, A, Fassi, E, Shinawi, M, Constantino, JN, De Zorzi, R, Fortuna, S, Kok, F, Keren, B, Bonneau, D, Choi, M, Benzeev, B, Zara, F, Mefford, HC, Scheffer, IE, Clayton-Smith, J, Macaya, A, Rothman, JE, Eichler, EE, Kullmann, DM, Houlden, H, Raspall-Chaure, M, Hanna, MG, Bugiardini, E, Hostettler, I, O'Callaghan, B, Khan, A, Cortese, A, O'Connor, E, Yau, WY, Bourinaris, T, Kaiyrzhanov, R, Chelban, V, Madej, M, Diana, MC, Vari, MS, Pedemonte, M, Bruno, C, Balagura, G, Scala, M, Fiorillo, C, Nobili, L, Malintan, NT, Zanetti, MN, Krishnakumar, SS, Lignani, G, Jepson, JEC, Broda, P, Baldassari, S, Rossi, P, Fruscione, F, Madia, F, Traverso, M, De-Marco, P, Perez-Duenas, B, Munell, F, Kriouile, Y, El-Khorassani, M, Karashova, B, Avdjieva, D, Kathom, H, Tincheva, R, Van-Maldergem, L, Nachbauer, W, Boesch, S, Gagliano, A, Amadori, E, Goraya, JS, Sultan, T, Kirmani, S, Ibrahim, S, Jan, F, Mine, J, Banu, S, Veggiotti, P, Zuccotti, G, Ferrari, MD, Van Den Maagdenberg, AMJ, Verrotti, A, Marseglia, GL, Savasta, S, Soler, MA, Scuderi, C, Borgione, E, Chimenz, R, Gitto, E, Dipasquale, V, Sallemi, A, Fusco, M, Cuppari, C, Cutrupi, MC, Ruggieri, M, Cama, A, Capra, V, Mencacci, NE, Boles, R, Gupta, N, Kabra, M, Papacostas, S, Zamba-Papanicolaou, E, Dardiotis, E, Maqbool, S, Rana, N, Atawneh, O, Lim, SY, Shaikh, F, Koutsis, G, Breza, M, Coviello, DA, Dauvilliers, YA, AlKhawaja, I, AlKhawaja, M, Al-Mutairi, F, Stojkovic, T, Ferrucci, V, Zollo, M, Alkuraya, FS, Kinali, M, Sherifa, H, Benrhouma, H, Turki, IBY, Tazir, M, Obeid, M, Bakhtadze, S, Saadi, NW, Zaki, MS, Triki, CC, Benfenati, F, Gustincich, S, Kara, M, Belcastro, V, Specchio, N, Capovilla, G, Karimiani, EG, Salih, AM, Okubadejo, NU, Ojo, OO, Oshinaike, OO, Oguntunde, O, Wahab, K, Bello, AH, Abubakar, S, Obiabo, Y, Nwazor, E, Ekenze, O, Williams, U, Iyagba, A, Taiwo, L, Komolafe, M, Senkevich, K, Shashkin, C, Zharkynbekova, N, Koneyev, K, Manizha, G, Isrofilov, M, Guliyeva, U, Salayev, K, Khachatryan, S, Rossi, S, Silvestri, G, Haridy, N, Ramenghi, LA, Xiromerisiou, G, David, E, Aguennouz, M, Fidani, L, Spanaki, C, Tucci, A, Salpietro, V, Dixon, CL, Guo, H, Bello, OD, Vandrovcova, J, Efthymiou, S, Maroofian, R, Heimer, G, Burglen, L, Valence, S, Torti, E, Hacke, M, Rankin, J, Tariq, H, Colin, E, Procaccio, V, Striano, P, Mankad, K, Lieb, A, Chen, S, Pisani, L, Bettencourt, C, Mannikko, R, Manole, A, Brusco, A, Grosso, E, Ferrero, GB, Armstrong-Moron, J, Gueden, S, Bar-Yosef, O, Tzadok, M, Monaghan, KG, Santiago-Sim, T, Person, RE, Cho, MT, Willaert, R, Yoo, Y, Chae, J-H, Quan, Y, Wu, H, Wang, T, Bernier, RA, Xia, K, Blesson, A, Jain, M, Motazacker, MM, Jaeger, B, Schneider, AL, Boysen, K, Muir, AM, Myers, CT, Gavrilova, RH, Gunderson, L, Schultz-Rogers, L, Klee, EW, Dyment, D, Osmond, M, Parellada, M, Llorente, C, Gonzalez-Penas, J, Carracedo, A, Van Haeringen, A, Ruivenkamp, C, Nava, C, Heron, D, Nardello, R, Iacomino, M, Minetti, C, Skabar, A, Fabretto, A, Chez, M, Tsai, A, Fassi, E, Shinawi, M, Constantino, JN, De Zorzi, R, Fortuna, S, Kok, F, Keren, B, Bonneau, D, Choi, M, Benzeev, B, Zara, F, Mefford, HC, Scheffer, IE, Clayton-Smith, J, Macaya, A, Rothman, JE, Eichler, EE, Kullmann, DM, Houlden, H, Raspall-Chaure, M, Hanna, MG, Bugiardini, E, Hostettler, I, O'Callaghan, B, Khan, A, Cortese, A, O'Connor, E, Yau, WY, Bourinaris, T, Kaiyrzhanov, R, Chelban, V, Madej, M, Diana, MC, Vari, MS, Pedemonte, M, Bruno, C, Balagura, G, Scala, M, Fiorillo, C, Nobili, L, Malintan, NT, Zanetti, MN, Krishnakumar, SS, Lignani, G, Jepson, JEC, Broda, P, Baldassari, S, Rossi, P, Fruscione, F, Madia, F, Traverso, M, De-Marco, P, Perez-Duenas, B, Munell, F, Kriouile, Y, El-Khorassani, M, Karashova, B, Avdjieva, D, Kathom, H, Tincheva, R, Van-Maldergem, L, Nachbauer, W, Boesch, S, Gagliano, A, Amadori, E, Goraya, JS, Sultan, T, Kirmani, S, Ibrahim, S, Jan, F, Mine, J, Banu, S, Veggiotti, P, Zuccotti, G, Ferrari, MD, Van Den Maagdenberg, AMJ, Verrotti, A, Marseglia, GL, Savasta, S, Soler, MA, Scuderi, C, Borgione, E, Chimenz, R, Gitto, E, Dipasquale, V, Sallemi, A, Fusco, M, Cuppari, C, Cutrupi, MC, Ruggieri, M, Cama, A, Capra, V, Mencacci, NE, Boles, R, Gupta, N, Kabra, M, Papacostas, S, Zamba-Papanicolaou, E, Dardiotis, E, Maqbool, S, Rana, N, Atawneh, O, Lim, SY, Shaikh, F, Koutsis, G, Breza, M, Coviello, DA, Dauvilliers, YA, AlKhawaja, I, AlKhawaja, M, Al-Mutairi, F, Stojkovic, T, Ferrucci, V, Zollo, M, Alkuraya, FS, Kinali, M, Sherifa, H, Benrhouma, H, Turki, IBY, Tazir, M, Obeid, M, Bakhtadze, S, Saadi, NW, Zaki, MS, Triki, CC, Benfenati, F, Gustincich, S, Kara, M, Belcastro, V, Specchio, N, Capovilla, G, Karimiani, EG, Salih, AM, Okubadejo, NU, Ojo, OO, Oshinaike, OO, Oguntunde, O, Wahab, K, Bello, AH, Abubakar, S, Obiabo, Y, Nwazor, E, Ekenze, O, Williams, U, Iyagba, A, Taiwo, L, Komolafe, M, Senkevich, K, Shashkin, C, Zharkynbekova, N, Koneyev, K, Manizha, G, Isrofilov, M, Guliyeva, U, Salayev, K, Khachatryan, S, Rossi, S, Silvestri, G, Haridy, N, Ramenghi, LA, Xiromerisiou, G, David, E, Aguennouz, M, Fidani, L, Spanaki, C, and Tucci, A

Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

Published
2019

26. PRIMA1 mutation: A new cause of nocturnal frontal lobe epilepsy

Author

Hildebrand, M.S., Tankard, R., Gazina, E.V., Damiano, J.A., Lawrence, K.M., Dahl, H-H.M., Regan, B.M., Shearer, A.E., Smith, R.J.H., Marini, C., Guerrini, R., Labate, A., Gambardella, A., Tinuper, P., Lichetta, L., Baldassari, S., Bisulli, F., Pippucci, T., Scheffer, I.E., Reid, C.A., Petrou, S., Bahlo, M., Berkovic, S.F., Hildebrand, M.S., Tankard, R., Gazina, E.V., Damiano, J.A., Lawrence, K.M., Dahl, H-H.M., Regan, B.M., Shearer, A.E., Smith, R.J.H., Marini, C., Guerrini, R., Labate, A., Gambardella, A., Tinuper, P., Lichetta, L., Baldassari, S., Bisulli, F., Pippucci, T., Scheffer, I.E., Reid, C.A., Petrou, S., Bahlo, M., and Berkovic, S.F.

Abstract

Objective Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene. Methods Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. Results Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the PRIMA1 gene on chromosome 14. No additional PRIMA1 mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the PRIMA1 mRNA using a minigene system. Interpretation PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of PRIMA1. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first PRIMA1 mutation implicated in disease.

Published
2015

27. PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy

Author

Hildebrand, MS, Tankard, R, Gazina, EV, Damiano, JA, Lawrence, KM, Dahl, H-HM, Regan, BM, Shearer, AE, Smith, RJH, Marini, C, Guerrini, R, Labate, A, Gambardella, A, Tinuper, P, Lichetta, L, Baldassari, S, Bisulli, F, Pippucci, T, Scheffer, IE, Reid, CA, Petrou, S, Bahlo, M, Berkovic, SF, Hildebrand, MS, Tankard, R, Gazina, EV, Damiano, JA, Lawrence, KM, Dahl, H-HM, Regan, BM, Shearer, AE, Smith, RJH, Marini, C, Guerrini, R, Labate, A, Gambardella, A, Tinuper, P, Lichetta, L, Baldassari, S, Bisulli, F, Pippucci, T, Scheffer, IE, Reid, CA, Petrou, S, Bahlo, M, and Berkovic, SF

Abstract

OBJECTIVE: Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene. METHODS: Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. RESULTS: Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the PRIMA1 gene on chromosome 14. No additional PRIMA1 mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the PRIMA1 mRNA using a minigene system. INTERPRETATION: PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of PRIMA1. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first PRIMA1 mutation implicated in disease.

Published
2015

28. Epilepsy with auditory features: A heterogeneous clinico-molecular disease.

Author

Pippucci, T, Licchetta, L, Baldassari, S, Palombo, F, Menghi, V, D'Aurizio, R, Leta, C, Stipa, C, Boero, G, d'Orsi, G, Magi, A, Scheffer, I, Seri, M, Tinuper, P, Bisulli, F, Pippucci, T, Licchetta, L, Baldassari, S, Palombo, F, Menghi, V, D'Aurizio, R, Leta, C, Stipa, C, Boero, G, d'Orsi, G, Magi, A, Scheffer, I, Seri, M, Tinuper, P, and Bisulli, F

Abstract

OBJECTIVE: To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis. METHODS: We identified 15 probands with EAF in whom an LGI1 mutation had been excluded. We performed electroclinical phenotyping on all probands and available affected relatives. We used whole-exome sequencing (WES) in 20 individuals with EAF (including all the probands and 5 relatives) to identify single nucleotide variants, small insertions/deletions, and copy number variants. RESULTS: WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a CNTNAP2 intragenic deletion, 2 truncating mutations of DEPDC5, and a missense SCN1A change. CONCLUSIONS: EAF is a clinically and molecularly heterogeneous disease. The association of EAF with CNTNAP2, DEPDC5, and SCN1A mutations widens the phenotypic spectrum related to these genes. CNTNAP2 encodes CASPR2, a member of the voltage-gated potassium channel complex in which LGI1 plays a role. The finding of a CNTNAP2 deletion emphasizes the importance of this complex in EAF and shows biological convergence.

Published
2015

29. Progetto Child: la comunicazione della diagnosi al bambino sieropositivo

Author

Duse, Marzia, Badolato, R, Schumacher, F, Patuelli, L, Boldrini, M, Sgorbati, C, Coppini, S, Longhi, D, Brambilla, V., Rosa, E., Guarino, Angela, Officioso, N, Galli, L, Damico, E, Lipreri, R., CASTELLI GATTINARA, G, Baldassari, S, Osimani, P, and Sebastianelli, S.

Published
2006

37. Novel FAM126A mutations in hypomyelination and congenital cataract disease

Author

Traverso, M., primary, Assereto, S., additional, Gazzerro, E., additional, Savasta, S., additional, Abdalla, E.M., additional, Rossi, A., additional, Baldassari, S., additional, Fruscione, F., additional, Ruffinazzi, G., additional, Fassad, M.R., additional, El Beheiry, A., additional, Minetti, C., additional, Zara, F., additional, and Biancheri, R., additional

Published
2013
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43. DOE analyses on aqueous suspensions of TiO2 nanoparticles

Author

Baldassari, S., Corradi, A. Bonamartini, Bondioli, F., Ferrari, A.M., Romagnoli, M., and Villa, C.

Subjects
*TITANIUM dioxide, *NANOPARTICLES, *EXPERIMENTAL design, *POWDERS, *X-ray diffraction, *CELLULOSE, *HYDROLYSIS
Abstract

Abstract: Nanosized titanium oxide (TiO2) powders have been prepared by conventional and microwave hydrothermal methods by forced hydrolysis of TiOCl2. As-prepared powders have been completely characterised by qualitative and quantitative XRD and TEM. The obtained titania powders have been redispersed (45 and 60wt.%) in an aqueous hydroxypropylcellulose (HPC) solution (0.5–1wt.%). Rheological characterisation has been performed in order to evaluate the influence of HPC on particles agglomerations. The effect of mixing time, HPC and TiO2 concentration and their mutual interactions on shear stress have been evaluated with a design of experiment (DOE) approach. [Copyright &y& Elsevier]

Published
2008
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45. Renal function in HIV-infected children and adolescents treated with tenofovir disoproxil fumarate and protease inhibitors

Author

Pontrelli Giuseppe, Cotugno Nicola, Amodio Donato, Zangari Paola, Tchidjou Hyppolite K, Baldassari Stefania, Palma Paolo, and Bernardi Stefania

Subjects
Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Kidney disease is an important complication in HIV infected people, and this may be related to infection or antiretroviral therapy (ART). Our aim is to assess renal function in HIV infected paediatric patients, who may be particularly affected and are likely to take ART for longer than adults, and investigate the long term role of Tenofovir Disoproxil Fumarate (TDF) alone or co-administered with Ritonavir-boosted Protease Inhibitors (PI). Methods Serum creatinine, phosphate and potassium levels, with estimated Glomerular Filtration Rate (eGFR), had been prospectively evaluated for 2 years in a cohort of HIV infected children and adolescents (age 9-18) on ART, and data analyzed according to the exposure to TDF or simultaneous TDF and PI. Results Forty-nine patients were studied (57% female, mean age 14). Sixty-three percent were treated with ART containing TDF (Group A), and 37% without TDF (Group B); 47% with concomitant use of TDF and PI (Group C) and 53% without this combination (Group D). The groups didn't differ for age, gender or ethnicity. The median creatinine increased in the entire cohort and in all the groups analyzed; eGFR decreased from 143.6 mL/min/1.73 m2 at baseline to 128.9 after 2 years (p = 0.006) in the entire cohort. Three patients presented a mild eGFR reduction, all were on TDF+PI. Phosphatemia decreased significantly in the entire cohort (p = 0.0003) and in TDF+PI group (p = 0.0128) after 2 years. Five patients (10%) developed hypophosphatemia (Division of Acquired Immune Deficiency AE grade 1 or 2), and four of them were on TDF+PI. Conclusions Renal function decrease and hypophosphatemia occur over time in HIV infected children and adolescents on ART. The association with co-administration of TDF and PI appears weak, and further studies are warranted.

Published
2012
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46. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Author

Marina A. J. Tijssen, Mark A. Corbett, Zaid Afawi, Paolo Tinuper, Shoji Tsuji, Rachel Straussberg, Ilan Blatt, Samuel F. Berkovic, Francesco Brancati, Amy L Schneider, Lynette G. Sadleir, Sanjay M. Sisodiya, Renzo Guerrini, Shreyasee Chakraborty, Alfredo Berardelli, Silvana Franceschetti, Jozef Gecz, Luciano Xumerle, Pierre Labauge, Liana Veneziano, Simona Balestrini, Ingo Helbig, Martin A. Smith, Laura Canafoglia, Carlo Di Bonaventura, Hiroyuki Ishiura, Boris Keren, Manuela Pendziwiat, Rahel T. Florian, Sylvie Forlani, Anne Fleur van Rootselaar, Giorgio Casari, Christel Depienne, Tommaso Pippucci, Douglas E. Crompton, Edouard Hirsch, Davide Mei, Laura Licchetta, Renee Carroll, Riaan van Coller, Ingrid E. Scheffer, Thessa Kroes, Pasquale Striano, Brigid M. Regan, Francesca Bisulli, Shaun Carswell, Antonio Suppa, Julien Buratti, Karl Martin Klein, Alison Gardner, Caroline Nava, Federico Zara, Melanie Bahlo, Sabine Kaya, Kathryn Friend, Antonietta Coppola, Massimo Delledonne, Aaron M. Wenger, Anthony Correll, Sara Baldassari, Arn M. J. M. van den Maagdenberg, Eric LeGuern, Rachael Catford, Gabrielle Rudolf, Salvatore Striano, Mark F. Bennett, Josemir W. Sander, Kirston Barton, Michele Iacomino, Corbett M.A., Kroes T., Veneziano L., Bennett M.F., Florian R., Schneider A.L., Coppola A., Licchetta L., Franceschetti S., Suppa A., Wenger A., Mei D., Pendziwiat M., Kaya S., Delledonne M., Straussberg R., Xumerle L., Regan B., Crompton D., van Rootselaar A.-F., Correll A., Catford R., Bisulli F., Chakraborty S., Baldassari S., Tinuper P., Barton K., Carswell S., Smith M., Berardelli A., Carroll R., Gardner A., Friend K.L., Blatt I., Iacomino M., Di Bonaventura C., Striano S., Buratti J., Keren B., Nava C., Forlani S., Rudolf G., Hirsch E., Leguern E., Labauge P., Balestrini S., Sander J.W., Afawi Z., Helbig I., Ishiura H., Tsuji S., Sisodiya S.M., Casari G., Sadleir L.G., van Coller R., Tijssen M.A.J., Klein K.M., van den Maagdenberg A.M.J.M., Zara F., Guerrini R., Berkovic S.F., Pippucci T., Canafoglia L., Bahlo M., Striano P., Scheffer I.E., Brancati F., Depienne C., Gecz J., Neurology, ANS - Brain Imaging, Movement Disorder (MD), Corbett, M. A., Kroes, T., Veneziano, L., Bennett, M. F., Florian, R., Schneider, A. L., Coppola, A., Licchetta, L., Franceschetti, S., Suppa, A., Wenger, A., Mei, D., Pendziwiat, M., Kaya, S., Delledonne, M., Straussberg, R., Xumerle, L., Regan, B., Crompton, D., van Rootselaar, A. -F., Correll, A., Catford, R., Bisulli, F., Chakraborty, S., Baldassari, S., Tinuper, P., Barton, K., Carswell, S., Smith, M., Berardelli, A., Carroll, R., Gardner, A., Friend, K. L., Blatt, I., Iacomino, M., Di Bonaventura, C., Striano, S., Buratti, J., Keren, B., Nava, C., Forlani, S., Rudolf, G., Hirsch, E., Leguern, E., Labauge, P., Balestrini, S., Sander, J. W., Afawi, Z., Helbig, I., Ishiura, H., Tsuji, S., Sisodiya, S. M., Casari, G., Sadleir, L. G., van Coller, R., Tijssen, M. A. J., Klein, K. M., van den Maagdenberg, A. M. J. M., Zara, F., Guerrini, R., Berkovic, S. F., Pippucci, T., Canafoglia, L., Bahlo, M., Striano, P., Scheffer, I. E., Brancati, F., Depienne, C., and Gecz, J.

Subjects
0301 basic medicine, Male, Myoclonus, Medizin, General Physics and Astronomy, Epilepsies, Myoclonic, Epilepsies, Intronic variant, repeat expansions,STARD7, familial adult myoclonic epilepsy, chromosome 2, Epilepsy, 0302 clinical medicine, DOMINANT CORTICAL TREMOR, EXPRESSION ANALYSIS, PEDIGREE, LOCUS, LINKAGE, GENE, 2P11.1-Q12.2, REFINEMENT, MUTATION, BAFME, lcsh:Science, Child, Genetics, Multidisciplinary, DNA Repeat Expansion, Disease genetics, Chromosome Mapping, Middle Aged, Pedigree, Myoclonic Epilepsy, Child, Preschool, Chromosomes, Human, Pair 2, Pair 2, STARD7, Female, Adolescent, Adult, Carrier Proteins, Humans, Young Adult, Introns, Human, Science, Locus (genetics), Biology, Chromosomes, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Preschool, Gene, Whole genome sequencing, Intron, Chromosome, General Chemistry, medicine.disease, 030104 developmental biology, Microsatellite instability, Myoclonic epilepsy, lcsh:Q, Familial Adult Myoclonic Epilepsy, Myoclonic, Carrier Protein, 030217 neurology & neurosurgery, Neurological disorders
Abstract

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved., Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al. identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”

Published
2019

47. Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy

Author

Luca Gozzelino, Gaga Kochlamazashvili, Sara Baldassari, Albert Ian Mackintosh, Laura Licchetta, Emanuela Iovino, Yu Chi Liu, Caitlin A Bennett, Mark F Bennett, John A Damiano, Gábor Zsurka, Caterina Marconi, Tania Giangregorio, Pamela Magini, Marijn Kuijpers, Tanja Maritzen, Giuseppe Danilo Norata, Stéphanie Baulac, Laura Canafoglia, Marco Seri, Paolo Tinuper, Ingrid E Scheffer, Melanie Bahlo, Samuel F Berkovic, Michael S Hildebrand, Wolfram S Kunz, Lucio Giordano, Francesca Bisulli, Miriam Martini, Volker Haucke, Emilio Hirsch, Tommaso Pippucci, Gozzelino L., Kochlamazashvili G., Baldassari S., Mackintosh A.I., Licchetta L., Iovino E., Liu Y.-C., Bennett C.A., Bennett M.F., Damiano J.A., Zsurka G., Marconi C., Giangregorio T., Magini P., Kuijpers M., Maritzen T., Norata G.D., Baulac S., Canafoglia L., Seri M., Tinuper P., Scheffer I.E., Bahlo M., Berkovic S.F., Hildebrand M.S., Kunz W.S., Giordano L., Bisulli F., Martini M., Haucke V., Hirsch E., and Pippucci T.

Subjects
PI3K-C2B, class II PI3K, epilepsy, mTOR, variants, Animals, Humans, Lipids, Mechanistic Target of Rapamycin Complex 1, Mice, Mutation, Phosphatidylinositol 3-Kinases, Seizures, Class II Phosphatidylinositol 3-Kinases, Epilepsies, Partial, Epilepsies, Animal, Lipid, Seizure, variant, Class II Phosphatidylinositol 3-Kinase, Settore BIO/14 - Farmacologia, Neurology (clinical), Phosphatidylinositol 3-Kinase, Human, Partial
Abstract

Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated.Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients’ variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy.Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.

Published
2022

48. Epilepsy with auditory features: Contribution of known genes in 112 patients

Author

Barbara Mostacci, Leonardo Caporali, Raffaella Minardi, Paolo Tinuper, Corrado Zenesini, Lorenzo Muccioli, Martina Fanella, S. Baldassari, Laura Licchetta, C. Rinaldi, Tommaso Pippucci, Veronica Menghi, Patrizia Avoni, Francesca Bisulli, Bisulli F., Rinaldi C., Pippucci T., Minardi R., Baldassari S., Zenesini C., Mostacci B., Fanella M., Avoni P., Menghi V., Caporali L., Muccioli L., Tinuper P., and Licchetta L.

Subjects
Male, Proband, DEPDC5, Epilepsy, Frontal Lobe, RELN, Bioinformatics, Genetic analysis, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic, Next generation sequencing, medicine, Humans, genetics, SCN1A, LGI1, next generation sequencing, Genetic heterogeneity, business.industry, General Medicine, medicine.disease, Penetrance, Pedigree, Reelin Protein, Neurology, Mutation, Epilepsy syndromes, Cohort, Female, Neurology (clinical), business, Epileptic Syndromes, 030217 neurology & neurosurgery
Abstract

Epilepsy with Auditory Features (EAF) is a focal epilepsy syndrome mainly of unknown aetiology. LGI1 and RELN have been identified as the main cause of Autosomal Dominant EAF and anecdotally reported in non-familial cases. Pathogenic variants in SCN1A and DEPDC5 have also been described in a few EAF probands belonging to families with heterogeneous phenotypes and incomplete penetrance. We aimed to estimate the contribution of these genes to the disorder by evaluating the largest cohort of EAF. We included 112 unrelated EAF cases (male/female: 52/60) who underwent genetic analysis by next-generation sequencing (NGS) techniques. Thirty-three (29.5%) were familial cases. We identified a genetic diagnosis for 8% of our cohort, including pathogenic/likely pathogenic variants (4/8 novel) in LGI1 (2.7%, CI: 0.6-7.6); RELN (1.8%; CI: 0.2-6.3); SCN1A (2.7%; CI: 0.6-7.6) and DEPDC5 (0.9%; CI 0-4.9).This study shows that the contribution of each of the known genes to the overall disorder is limited and that the genetic background of EAF is still largely unknown. Our data emphasize the genetic heterogeneity of EAF and will inform the diagnosis and management of individuals with this disorder.

Published
2021

49. Targeting Alternative Splicing as a Potential Therapy for Episodic Ataxia Type 2

Author

Ilaria Musante, Lorenzo A. Cingolani, Fanny Jaudon, Federico Zara, Simona Baldassari, Agnes Thalhammer, Jaudon, F., Baldassari, S., Musante, I., Thalhammer, A., Zara, F., and Cingolani, L. A.

Subjects
0301 basic medicine, Ataxia, Alternative splicing, Antisense oligonucleotides, CRISPR/Cas9, Episodic ataxia type 2, P/Q-type Ca2+channels, SMaRT, Duchenne muscular dystrophy, P/Q-type Ca2+channel, Medicine (miscellaneous), Review, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, alternative splicing, 0302 clinical medicine, medicine, Antisense oligonucleotide, P/Q-type Ca2+ channels, Muscular dystrophy, lcsh:QH301-705.5, Gene, business.industry, Parkinsonism, medicine.disease, 030104 developmental biology, episodic ataxia type 2, lcsh:Biology (General), RNA splicing, medicine.symptom, antisense oligonucleotides, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by paroxysmal attacks of ataxia, vertigo, and nausea that usually last hours to days. It is caused by loss-of-function mutations in CACNA1A, the gene encoding the pore-forming α1 subunit of P/Q-type voltage-gated Ca2+ channels. Although pharmacological treatments, such as acetazolamide and 4-aminopyridine, exist for EA2, they do not reduce or control the symptoms in all patients. CACNA1A is heavily spliced and some of the identified EA2 mutations are predicted to disrupt selective isoforms of this gene. Modulating splicing of CACNA1A may therefore represent a promising new strategy to develop improved EA2 therapies. Because RNA splicing is dysregulated in many other genetic diseases, several tools, such as antisense oligonucleotides, trans-splicing, and CRISPR-based strategies, have been developed for medical purposes. Here, we review splicing-based strategies used for genetic disorders, including those for Duchenne muscular dystrophy, spinal muscular dystrophy, and frontotemporal dementia with Parkinsonism linked to chromosome 17, and discuss their potential applicability to EA2.

Published
2020

50. Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development

Author

Michele Iacomino, Simona Baldassari, Yuki Tochigi, Katarzyna Kośla, Francesca Buffelli, Annalaura Torella, Mariasavina Severino, Dario Paladini, Luana Mandarà, Antonella Riva, Marcello Scala, Ganna Balagura, Andrea Accogli, Vincenzo Nigro, Carlo Minetti, Ezio Fulcheri, Federico Zara, Andrzej K. Bednarek, Pasquale Striano, Hiroetsu Suzuki, Vincenzo Salpietro, Iacomino, M., Baldassari, S., Tochigi, Y., Kosla, K., Buffelli, F., Torella, A., Severino, M., Paladini, D., Mandara, L., Riva, A., Scala, M., Balagura, G., Accogli, A., Nigro, V., Minetti, C., Fulcheri, E., Zara, F., Bednarek, A. K., Striano, P., Suzuki, H., and Salpietro, V.

Subjects
0301 basic medicine, WWOX, Cell, Biology, medicine.disease_cause, lcsh:RC321-571, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, medicine, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Gene, Mutation, neuropathology, General Neuroscience, animal model, cytoskeleton, WOREE syndrome, Brief Research Report, Neural stem cell, Cell biology, developing brain, 030104 developmental biology, medicine.anatomical_structure, Cerebral cortex, Neural development, 030217 neurology & neurosurgery, Neuroscience
Abstract

Mutations in the WWOX gene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumor suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygous WWOX mutation leading to a premature stop codon. Abnormal cerebral cortex development due to a defective architecture of granular and molecular cell layers was found in the developing brain of a WWOX-deficient human fetus from this family. A similar disorganization of cortical layers was identified in lde/lde rats (carrying a homozygous truncating mutation which disrupts the active Wwox C-terminal domain) investigated at perinatal stages. Transcriptomic analyses of Wwox-depleted human neural progenitor cells showed an impaired expression of a number of neuronal migration-related genes encoding for tubulins, kinesins and associated proteins. These findings indicate that loss of Wwox may affect different cytoskeleton components and alter prenatal cortical development, highlighting a regulatory role of the WWOX gene in migrating neurons across different species.

Published
2020

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