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8 results on '"Issa, M.Y."'

2. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author

Scala, M., Wortmann, S.B., Kaya, N., Stellingwerff, M.D., Pistorio, A., Glamuzina, E., Karnebeek, C.D. van, Skrypnyk, C., Iwanicka-Pronicka, K., Piekutowska-Abramczuk, D., Ciara, E., Tort, F., Sheidley, B., Poduri, A., Jayakar, P., Jayakar, A., Upadia, J., Walano, N., Haack, T.B., Prokisch, H., Aldhalaan, H., Karimiani, E.G., Yildiz, Y., Ceylan, A.C., Santiago-Sim, T., Dameron, A., Yang, H., Toosi, M.B., Ashrafzadeh, F., Akhondian, J., Imannezhad, S., Mirzadeh, H.S., Maqbool, S., Farid, A., Al-Muhaizea, M.A., Alshwameen, M.O., Aldowsari, L., Alsagob, M., Alyousef, A., Almass, R., AlHargan, A., Alwadei, A.H., AlRasheed, M.M., Colak, D., Alqudairy, H., Khan, S., Lines, M.A., Cazorla, M., Ribes, A., Morava, E., Bibi, F., Haider, S., Ferla, M.P., Taylor, J.C., Alsaif, H.S., Firdous, A., Hashem, M., Shashkin, C., Koneev, K., Kaiyrzhanov, R., Efthymiou, S., Genomics, Q.S., Schmitt-Mechelke, T., Ziegler, A., Issa, M.Y., Elbendary, H.M., Striano, P., Alkuraya, F.S., Zaki, M.S., Gleeson, J.G., Barakat, T.S., Bierau, J., Knaap, M.S. van der, Maroofian, R., Houlden, H., Scala, M., Wortmann, S.B., Kaya, N., Stellingwerff, M.D., Pistorio, A., Glamuzina, E., Karnebeek, C.D. van, Skrypnyk, C., Iwanicka-Pronicka, K., Piekutowska-Abramczuk, D., Ciara, E., Tort, F., Sheidley, B., Poduri, A., Jayakar, P., Jayakar, A., Upadia, J., Walano, N., Haack, T.B., Prokisch, H., Aldhalaan, H., Karimiani, E.G., Yildiz, Y., Ceylan, A.C., Santiago-Sim, T., Dameron, A., Yang, H., Toosi, M.B., Ashrafzadeh, F., Akhondian, J., Imannezhad, S., Mirzadeh, H.S., Maqbool, S., Farid, A., Al-Muhaizea, M.A., Alshwameen, M.O., Aldowsari, L., Alsagob, M., Alyousef, A., Almass, R., AlHargan, A., Alwadei, A.H., AlRasheed, M.M., Colak, D., Alqudairy, H., Khan, S., Lines, M.A., Cazorla, M., Ribes, A., Morava, E., Bibi, F., Haider, S., Ferla, M.P., Taylor, J.C., Alsaif, H.S., Firdous, A., Hashem, M., Shashkin, C., Koneev, K., Kaiyrzhanov, R., Efthymiou, S., Genomics, Q.S., Schmitt-Mechelke, T., Ziegler, A., Issa, M.Y., Elbendary, H.M., Striano, P., Alkuraya, F.S., Zaki, M.S., Gleeson, J.G., Barakat, T.S., Bierau, J., Knaap, M.S. van der, Maroofian, R., and Houlden, H.

Abstract

Contains fulltext : 283128.pdf (Publisher’s version ) (Open Access), Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Published
2022

4. Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration

Author

Shashi, V., Magiera, M.M., Klein, D., Zaki, M., Schoch, K., Rudnik-Schoneborn, S., Norman, A., Neto, O. Abath, Dusl, M., Yuan, X., Bartesaghi, L., Marco, P. De, Alfares, A.A., Marom, R., Arold, Stefan T., Guzman-Vega, F.J., Pena, L.D., Smith, E.C., Steinlin, M., Babiker, M.O., Mohassel, P., Foley, A.R., Donkervoort, S., Kaur, R., Ghosh, P.S., Stanley, V., Musaev, D., Nava, C., Mignot, C., Keren, B., Scala, M., Tassano, E., Picco, P., Doneda, P., Fiorillo, C., Issa, M.Y., Alassiri, A., Alahmad, A., Gerard, A., Liu, P, Yang, Y., Ertl-Wagner, B., Kranz, P.G., Wentzensen, I.M., Stucka, R., Stong, N., Allen, A.S., Goldstein, D.B, Schoser, B., Rosler, K.M., Alfadhel, M., Capra, V., Chrast, R., Strom, T.M., Kamsteeg, E.J., Bonnemann, C.G., Gleeson, J.G., Martini, R., Janke, C., Senderek, J., Shashi, V., Magiera, M.M., Klein, D., Zaki, M., Schoch, K., Rudnik-Schoneborn, S., Norman, A., Neto, O. Abath, Dusl, M., Yuan, X., Bartesaghi, L., Marco, P. De, Alfares, A.A., Marom, R., Arold, Stefan T., Guzman-Vega, F.J., Pena, L.D., Smith, E.C., Steinlin, M., Babiker, M.O., Mohassel, P., Foley, A.R., Donkervoort, S., Kaur, R., Ghosh, P.S., Stanley, V., Musaev, D., Nava, C., Mignot, C., Keren, B., Scala, M., Tassano, E., Picco, P., Doneda, P., Fiorillo, C., Issa, M.Y., Alassiri, A., Alahmad, A., Gerard, A., Liu, P, Yang, Y., Ertl-Wagner, B., Kranz, P.G., Wentzensen, I.M., Stucka, R., Stong, N., Allen, A.S., Goldstein, D.B, Schoser, B., Rosler, K.M., Alfadhel, M., Capra, V., Chrast, R., Strom, T.M., Kamsteeg, E.J., Bonnemann, C.G., Gleeson, J.G., Martini, R., Janke, C., and Senderek, J.

Abstract

Item does not contain fulltext, A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

Published
2018

6. Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia.

Author

Marin-Valencia, I., Gerondopoulos, A., Zaki, M.S., Ben-Omran, T., Almureikhi, M., Demir, E., Guemez-Gamboa, A., Gregor, A., Issa, M.Y., Appelhof, B, Roosing, S., Musaev, D., Rosti, B., Wirth, S., Stanley, V., Baas, F., Barr, F.A., Gleeson, J.G., Marin-Valencia, I., Gerondopoulos, A., Zaki, M.S., Ben-Omran, T., Almureikhi, M., Demir, E., Guemez-Gamboa, A., Gregor, A., Issa, M.Y., Appelhof, B, Roosing, S., Musaev, D., Rosti, B., Wirth, S., Stanley, V., Baas, F., Barr, F.A., and Gleeson, J.G.

Abstract

Contains fulltext : 177360.pdf (publisher's version ) (Open Access)

Published
2017

7. Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects.

Author

Mori, R. de, Romani, M., D'Arrigo, S., Zaki, M.S., Lorefice, E., Tardivo, S., Biagini, T., Stanley, V., Musaev, D., Fluss, J., Micalizzi, A., Nuovo, S., Illi, B., Chiapparini, L., Marcotullio, L. Di, Issa, M.Y., Anello, D., Casella, A., Ginevrino, M., Leggins, A.S., Roosing, S., Alfonsi, R., Rosati, J., Schot, R., Mancini, G.M.S., Bertini, E., Dobyns, W.B., Mazza, T., Gleeson, J.G., Valente, E.M., Mori, R. de, Romani, M., D'Arrigo, S., Zaki, M.S., Lorefice, E., Tardivo, S., Biagini, T., Stanley, V., Musaev, D., Fluss, J., Micalizzi, A., Nuovo, S., Illi, B., Chiapparini, L., Marcotullio, L. Di, Issa, M.Y., Anello, D., Casella, A., Ginevrino, M., Leggins, A.S., Roosing, S., Alfonsi, R., Rosati, J., Schot, R., Mancini, G.M.S., Bertini, E., Dobyns, W.B., Mazza, T., Gleeson, J.G., and Valente, E.M.

Abstract

Contains fulltext : 182760.pdf (publisher's version ) (Open Access)

Published
2017

8. Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Author

De Mori, R. (Roberta), Romani, M. (Marta), D'Arrigo, S. (Stefano), Zaki, M.S. (Maha), Lorefice, E. (Elisa), Tardivo, S. (Silvia), Biagini, T. (Tommaso), Stanley, V. (Valentina), Musaev, D. (Damir), Fluss, J. (Joel), Micalizzi, A. (Alessia), Nuovo, S. (Sara), Illi, B. (Barbara), Chiapparini, L. (Luisa), Di Marcotullio, L. (Lucia), Issa, M.Y. (Mahmoud Y.), Anello, D. (Danila), Casella, A. (Antonella), Ginevrino, M. (Monia), Leggins, A.S. (Autumn Sa'na), Roosing, S. (Susanne), Alfonsi, R. (Romina), Rosati, J. (Jessica), Schot, R. (Rachel), Mancini, G.M.S. (Grazia), Bertini, E. (Enrico), Dobyns, W.B. (William), Mazza, T. (Tommaso), Gleeson, J.G. (Joseph G.), Valente, J. (José), De Mori, R. (Roberta), Romani, M. (Marta), D'Arrigo, S. (Stefano), Zaki, M.S. (Maha), Lorefice, E. (Elisa), Tardivo, S. (Silvia), Biagini, T. (Tommaso), Stanley, V. (Valentina), Musaev, D. (Damir), Fluss, J. (Joel), Micalizzi, A. (Alessia), Nuovo, S. (Sara), Illi, B. (Barbara), Chiapparini, L. (Luisa), Di Marcotullio, L. (Lucia), Issa, M.Y. (Mahmoud Y.), Anello, D. (Danila), Casella, A. (Antonella), Ginevrino, M. (Monia), Leggins, A.S. (Autumn Sa'na), Roosing, S. (Susanne), Alfonsi, R. (Romina), Rosati, J. (Jessica), Schot, R. (Rachel), Mancini, G.M.S. (Grazia), Bertini, E. (Enrico), Dobyns, W.B. (William), Mazza, T. (Tommaso), Gleeson, J.G. (Joseph G.), and Valente, J. (José)

Abstract

The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.

Published
2017
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