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32 results on '"Froukh, Tawfiq"'

1. Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy

Author

Banks, Emily, Francis, Vincent, Lin, Sheng-Jia, Kharfallah, Fares, Fonov, Vladimir, Lévesque, Maxime, Han, Chanshuai, Kulasekaran, Gopinath, Tuznik, Marius, Bayati, Armin, Al-Khater, Reem, Alkuraya, Fowzan S., Argyriou, Loukas, Babaei, Meisam, Bahlo, Melanie, Bakhshoodeh, Behnoosh, Barr, Eileen, Bartik, Lauren, Bassiony, Mahmoud, Bertrand, Miriam, Braun, Dominique, Buchert, Rebecca, Budetta, Mauro, Cadieux-Dion, Maxime, Calame, Daniel G., Cope, Heidi, Cushing, Donna, Efthymiou, Stephanie, Elmaksoud, Marwa Abd, El Said, Huda G., Froukh, Tawfiq, Gill, Harinder K., Gleeson, Joseph G., Gogoll, Laura, Goh, Elaine S.-Y., Gowda, Vykuntaraju K., Haack, Tobias B., Hashem, Mais O., Hauser, Stefan, Hoffman, Trevor L., Hogue, Jacob S., Hosokawa, Akimoto, Houlden, Henry, Huang, Kevin, Huynh, Stephanie, Karimiani, Ehsan G., Kaulfuß, Silke, Korenke, G. Christoph, Kritzer, Amy, Lee, Hane, Lupski, James R., Marco, Elysa J., McWalter, Kirsty, Minassian, Arakel, Minassian, Berge A., Murphy, David, Neira-Fresneda, Juanita, Northrup, Hope, Nyaga, Denis M., Oehl-Jaschkowitz, Barbara, Osmond, Matthew, Person, Richard, Pehlivan, Davut, Petree, Cassidy, Sadleir, Lynette G., Saunders, Carol, Schoels, Ludger, Shashi, Vandana, Spillmann, Rebecca C., Srinivasan, Varunvenkat M., Torbati, Paria N., Tos, Tulay, Zaki, Maha S., Zhou, Dihong, Zweier, Christiane, Trempe, Jean-François, Durcan, Thomas M., Gan-Or, Ziv, Avoli, Massimo, Alves, Cesar, Varshney, Gaurav K., Maroofian, Reza, Rudko, David A., and McPherson, Peter S.

Published
2024
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2. Skewed X-chromosome inactivation in unsolved neurodevelopmental disease cases can guide re-evaluation For X-linked genes

Author

Giovenino, Chiara, Trajkova, Slavica, Pavinato, Lisa, Cardaropoli, Simona, Pullano, Verdiana, Ferrero, Enza, Sukarova-Angelovska, Elena, Carestiato, Silvia, Salmin, Paola, Rinninella, Antonina, Battaglia, Anthony, Bertoli, Luca, Fadda, Antonio, Palermo, Flavia, Carli, Diana, Mussa, Alessandro, Dimartino, Paola, Bruselles, Alessandro, Froukh, Tawfiq, Mandrile, Giorgia, Pasini, Barbara, De Rubeis, Silvia, Buxbaum, Joseph D., Pippucci, Tommaso, Tartaglia, Marco, Rossato, Marzia, Delledonne, Massimo, Ferrero, Giovanni Battista, and Brusco, Alfredo

Published
2023
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3. Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Author

Chowdhury, Fuad, Wang, Lei, Al-Raqad, Mohammed, Amor, David J., Baxová, Alice, Bendová, Šárka, Biamino, Elisa, Brusco, Alfredo, Caluseriu, Oana, Cox, Nancy J., Froukh, Tawfiq, Gunay-Aygun, Meral, Hančárová, Miroslava, Haynes, Devon, Heide, Solveig, Hoganson, George, Kaname, Tadashi, Keren, Boris, Kosaki, Kenjiro, Kubota, Kazuo, Lemons, Jennifer M., Magriña, Maria A., Mark, Paul R., McDonald, Marie T., Montgomery, Sarah, Morley, Gina M., Ohnishi, Hidenori, Okamoto, Nobuhiko, Rodriguez-Buritica, David, Rump, Patrick, Sedláček, Zdeněk, Schatz, Krista, Streff, Haley, Uehara, Tomoko, Walia, Jagdeep S., Wheeler, Patricia G., Wiesener, Antje, Zweier, Christiane, Kawakami, Koichi, Wentzensen, Ingrid M., Lalani, Seema R., Siu, Victoria M., Bi, Weimin, and Balci, Tugce B.

Published
2021
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5. Skewed X-chromosome Inactivation in Unsolved Neurodevelopmental Disease Cases Can Guide Re-evaluation for X-linked Genes

Author

Brusco, Alfredo, primary, Giovenino, Chiara, additional, Trajkova, Slavica, additional, Pavinato, Lisa, additional, Cardaropoli, Simona, additional, Pullano, Verdiana, additional, Sukarova-Angelovska, Elena, additional, Carestiato, Silvia, additional, Salmin, Paola, additional, Rinninella, Antonina, additional, Battaglia, Anthony, additional, Bertoli, Luca, additional, Fadda, Antonio, additional, Palermo, Flavia, additional, Carli, Diana, additional, Mussa, Alessandro, additional, Dimartino, Paola, additional, Bruselles, Alessandro, additional, froukh, Tawfiq, additional, Mandrile, Giorgia, additional, Pasini, Barbara, additional, De Rubeis, Silvia, additional, Buxbaum, Joseph, additional, Pippucci, Tommaso, additional, Tartaglia, Marco, additional, Rossato, Marzia, additional, Delledonne, Massimo, additional, and Ferrero, Giovanni Battista, additional

Published
2022
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6. A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode

Author

Marafi, Dana, primary, Kozar, Nina, additional, Duan, Ruizhi, additional, Bradley, Stephen, additional, Yokochi, Kenji, additional, Al Mutairi, Fuad, additional, Saadi, Nebal Waill, additional, Whalen, Sandra, additional, Brunet, Theresa, additional, Kotzaeridou, Urania, additional, Choukair, Daniela, additional, Keren, Boris, additional, Nava, Caroline, additional, Kato, Mitsuhiro, additional, Arai, Hiroshi, additional, Froukh, Tawfiq, additional, Faqeih, Eissa Ali, additional, AlAsmari, Ali M., additional, Saleh, Mohammed M., additional, Pinto e Vairo, Filippo, additional, Pichurin, Pavel N., additional, Klee, Eric W., additional, Schmitz, Christopher T., additional, Grochowski, Christopher M., additional, Mitani, Tadahiro, additional, Herman, Isabella, additional, Calame, Daniel G., additional, Fatih, Jawid M., additional, Du, Haowei, additional, Coban-Akdemir, Zeynep, additional, Pehlivan, Davut, additional, Jhangiani, Shalini N., additional, Gibbs, Richard A., additional, Miyatake, Satoko, additional, Matsumoto, Naomichi, additional, Wagstaff, Laura J., additional, Posey, Jennifer E., additional, Lupski, James R., additional, Meijer, Dies, additional, and Wagner, Matias, additional

Published
2022
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7. Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

Author

Reuter, Miriam S., Tawamie, Hasan, Buchert, Rebecca, Hosny Gebril, Ola, Froukh, Tawfiq, Thiel, Christian, Uebe, Steffen, Ekici, Arif B., Krumbiegel, Mandy, Zweier, Christiane, Hoyer, Juliane, Eberlein, Karolin, Bauer, Judith, Scheller, Ute, Strom, Tim M., Hoffjan, Sabine, Abdelraouf, Ehab R., Meguid, Nagwa A., Abboud, Ahmad, Al Khateeb, Mohammed Ayman, Fakher, Mahmoud, Hamdan, Saber, Ismael, Amina, Muhammad, Safia, Abdallah, Ebtessam, Sticht, Heinrich, Wieczorek, Dagmar, Reis, André, and Abou Jamra, Rami

Published
2017
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8. Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes

Author

Laugwitz, Lucia, primary, Seibt, Annette, additional, Herebian, Diran, additional, Peralta, Susana, additional, Kienzle, Imke, additional, Buchert, Rebecca, additional, Falb, Ruth, additional, Gauck, Darja, additional, Müller, Amelie, additional, Grimmel, Mona, additional, Beck-Woedel, Stefanie, additional, Kern, Jan, additional, Daliri, Karim, additional, Katibeh, Pegah, additional, Danhauser, Katharina, additional, Leiz, Steffen, additional, Alesi, Viola, additional, Baertling, Fabian, additional, Vasco, Gessica, additional, Steinfeld, Robert, additional, Wagner, Matias, additional, Caglayan, Ahmet Okay, additional, Gumus, Hakan, additional, Burmeister, Margit, additional, Mayatepek, Ertan, additional, Martinelli, Diego, additional, Tamhankar, Parag Mohan, additional, Tamhankar, Vasundhara, additional, Joset, Pascal, additional, Steindl, Katharina, additional, Rauch, Anita, additional, Bonnen, Penelope E, additional, Froukh, Tawfiq, additional, Groeschel, Samuel, additional, Krägeloh-Mann, Ingeborg, additional, Haack, Tobias B, additional, and Distelmaier, Felix, additional

Published
2021
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9. Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy

Author

Rapp, Christina K., primary, Van Dijck, Ine, additional, Laugwitz, Lucia, additional, Boon, Mieke, additional, Briassoulis, George, additional, Ilia, Stavroula, additional, Kammer, Birgit, additional, Reu, Simone, additional, Hornung, Stefanie, additional, Buchert, Rebecca, additional, Sofan, Linda, additional, Froukh, Tawfiq, additional, Witters, Peter, additional, Rymen, Daisy, additional, Haack, Tobias B., additional, Proesmans, Marijke, additional, and Griese, Matthias, additional

Published
2021
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11. Homozygous TAF1C variants are associated with a novel childhood‐onset neurological phenotype

Author

Knuutinen, Oula, primary, Pyle, Angela, additional, Suo‐Palosaari, Maria, additional, Duff, Jennifer, additional, Froukh, Tawfiq, additional, Lehesjoki, Anna‐Elina, additional, Kangas, Salla M., additional, Cassidy, James, additional, Maraqa, Latifa, additional, Keski‐Filppula, Riikka, additional, Kokkonen, Hannaleena, additional, Uusimaa, Johanna, additional, Horvath, Rita, additional, and Vieira, Päivi, additional

Published
2020
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12. Genetic basis of neurodevelopmental disorders in 103 Jordanian families

Author

Froukh, Tawfiq, primary, Nafie, Omar, additional, Al Hait, Sana' A. S., additional, Laugwitz, Lucia, additional, Sommerfeld, Julia, additional, Sturm, Marc, additional, Baraghiti, Aya, additional, Issa, Tala, additional, Al‐Nazer, Anis, additional, Koch, Philipp A., additional, Hanselmann, Johannes, additional, Kootz, Beate, additional, Bauer, Peter, additional, Al‐Ameri, Wael, additional, Abou Jamra, Rami, additional, Alfrook, Ayman J., additional, Hamadallah, Moath, additional, Sofan, Linda, additional, Riess, Angelika, additional, Haack, Tobias B., additional, Riess, Olaf, additional, and Buchert, Rebecca, additional

Published
2020
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13. First Record Mutations in the Genes

Author

Froukh, Tawfiq

Subjects
0301 basic medicine, Adult, Male, Article Subject, DNA Copy Number Variations, lcsh:Medicine, Biology, General Biochemistry, Genetics and Molecular Biology, Amidohydrolases, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, medicine, Humans, Exome, Genetic Predisposition to Disease, Gene, Exome sequencing, Cerebroside-Sulfatase, Genetic testing, Genetics, Jordan, General Immunology and Microbiology, medicine.diagnostic_test, Leukodystrophy, lcsh:R, Homozygote, Infant, General Medicine, Leukodystrophy, Metachromatic, medicine.disease, Phenotype, White Matter, Canavan disease, Pedigree, Metachromatic leukodystrophy, 030104 developmental biology, Mutation, Female, 030217 neurology & neurosurgery, Mri findings, Research Article
Abstract

Leukodystrophies (LDs) are heterogeneous genetic disorders characterized by abnormal white matter in the central nervous system. Some of the LDs are progressive and often fatal. In general, LD is primarily diagnosed based on the neuroimaging; however, definitive diagnosis of the LD type is done using genetic testing such as next-generation sequencing. The aim of this study is to identify the genetic causes of LD in two independent Jordanian cases that exhibit MRI findings confirming LD with no definitive diagnosis using whole exome sequencing (WES). The most likely causative variants were identified. In one case, the homozygous pathogenic variant NM_000049.2:c.914C>A;p.Ala305Glu, which is previously reported in ClinVar, in the gene ASPA was identified causing Canavan disease. In the second case, the homozygous novel variant NM_000487.5:c.256C>G;p.Arg86Gly in the gene ARSA was identified causing metachromatic leukodystrophy. The two variants segregate in their families. The phenotypes of the two studied cases overlap with assigned diseases. The present study raises the importance of using WES to identify the precise neurodevelopmental diseases in Jordan.

Published
2018

18. Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes

Author

Laugwitz, Lucia, Seibt, Annette, Herebian, Diran, Peralta, Susana, Kienzle, Imke, Buchert, Rebecca, Falb, Ruth, Gauck, Darja, Mu¨ller, Amelie, Grimmel, Mona, Beck-Woedel, Stefanie, Kern, Jan, Daliri, Karim, Katibeh, Pegah, Danhauser, Katharina, Leiz, Steffen, Alesi, Viola, Baertling, Fabian, Vasco, Gessica, Steinfeld, Robert, Wagner, Matias, Caglayan, Ahmet Okay, Gumus, Hakan, Burmeister, Margit, Mayatepek, Ertan, Martinelli, Diego, Tamhankar, Parag Mohan, Tamhankar, Vasundhara, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Bonnen, Penelope E, Froukh, Tawfiq, Groeschel, Samuel, Kra¨geloh-Mann, Ingeborg, Haack, Tobias B, and Distelmaier, Felix

Abstract

BackgroundHuman coenzyme Q4 (COQ4) is essential for coenzyme Q10(CoQ10) biosynthesis. Pathogenic variants in COQ4cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency.MethodsClinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed.ResultsWe characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10and elevated levels of the metabolic intermediate 6-demethoxyubiquinone.ConclusionOur study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4variants. Due to the insufficient clinical response to oral CoQ10supplementation, alternative treatment strategies are warranted.

Published
2022
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19. Haploinsufficiency of PRR12causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Author

Chowdhury, Fuad, Wang, Lei, Al-Raqad, Mohammed, Amor, David J., Baxová, Alice, Bendová, Šárka, Biamino, Elisa, Brusco, Alfredo, Caluseriu, Oana, Cox, Nancy J., Froukh, Tawfiq, Gunay-Aygun, Meral, Hančárová, Miroslava, Haynes, Devon, Heide, Solveig, Hoganson, George, Kaname, Tadashi, Keren, Boris, Kosaki, Kenjiro, Kubota, Kazuo, Lemons, Jennifer M., Magriña, Maria A., Mark, Paul R., McDonald, Marie T., Montgomery, Sarah, Morley, Gina M., Ohnishi, Hidenori, Okamoto, Nobuhiko, Rodriguez-Buritica, David, Rump, Patrick, Sedláček, Zdeněk, Schatz, Krista, Streff, Haley, Uehara, Tomoko, Walia, Jagdeep S., Wheeler, Patricia G., Wiesener, Antje, Zweier, Christiane, Kawakami, Koichi, Wentzensen, Ingrid M., Lalani, Seema R., Siu, Victoria M., Bi, Weimin, and Balci, Tugce B.

Abstract

Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency.

Published
2021
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23. Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A

Author

Han, Chanshuai, primary, Alkhater, Reem, additional, Froukh, Tawfiq, additional, Minassian, Arakel G., additional, Galati, Melissa, additional, Liu, Rui Han, additional, Fotouhi, Maryam, additional, Sommerfeld, Julia, additional, Alfrook, Ayman J., additional, Marshall, Christian, additional, Walker, Susan, additional, Bauer, Peter, additional, Scherer, Stephen W., additional, Riess, Olaf, additional, Buchert, Rebecca, additional, Minassian, Berge A., additional, and McPherson, Peter S., additional

Published
2016
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24. Mutations in MBOAT7 , Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features

Author

Johansen, Anide, primary, Rosti, Rasim O., additional, Musaev, Damir, additional, Sticca, Evan, additional, Harripaul, Ricardo, additional, Zaki, Maha, additional, Çağlayan, Ahmet Okay, additional, Azam, Matloob, additional, Sultan, Tipu, additional, Froukh, Tawfiq, additional, Reis, André, additional, Popp, Bernt, additional, Ahmed, Iltaf, additional, John, Peter, additional, Ayub, Muhammad, additional, Ben-Omran, Tawfeg, additional, Vincent, John B., additional, Gleeson, Joseph G., additional, and Abou Jamra, Rami, additional

Published
2016
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26. Genetic population structure, gene flow, and evolutionary history of selected ornamental fish in the Red Sea

Author

Froukh, Tawfiq, Blohm, Dietmar, and Held, Christoph

Subjects
population expansion, conservation, isolation by distance, neutrality test, Strait of Bab-el-Mandab, effective migrants, aquarium trade, evolutionary origin, evolutionary lineages, re-colonisation, sequence divergence, ddc:570, Strait of Tiran, Arabian Peninsula, 570 Life sciences, biology, Serranidae, PLD, Pomacentridae, molecular phylogeny, coral reef
Abstract

The ornamental fishery is expanding rapidly in the Red Sea, and concerns about the possibility of overexploitation were raised. Marine protected areas (MPAs) were addressed as a potential solution to prevent overexploitation. However, the sources of stock recruitment are not well understood. This thesis aims to reveal the genetic population structure and the demographic connectivity in the endemic fish species of the Red Sea Larabicus quadrilineatus, and in the two common fish species Chromis viridis and Pseudanthias squamipinnis. The fish samples were obtained from five locations in the Red Sea. For comparison, additional samples of the two common species were obtained from two locations in the Indo-Malay Archipelago. Partial sequence of the mitochondrial control region was used as a molecular marker in the three studied species. The studied species exhibited high genetic diversity as inferred from the haplotype and nucleotide indices. Analysis of molecular variance (AMOVA) detected significant genetic variation between northern and central/southern populations of L. quadrilineatus (ΦCT = 0.01; P < 0.01), and between the populations in the Gulf of Aqaba and the Red Sea proper of P. squamipinnis (ΦST = 0.02; P < 0.01). In addition, AMOVA detected significant genetic variation between the Red Sea and the Indo-Malay Archipelago for both C. viridis (ΦCT = 0.462; P < 0.001) and P. squamipinnis (ΦST = 0.78; P < 0.001). Migration analysis in the Red Sea revealed (1) higher migration into the Gulf of Aqaba for all species; (2) higher northward migration for C. viridis and L. quadrilineatus; and higher southward migration in the Red Sea proper for P. squamipinnis. A significant relationship between the genetic versus the geographic distances was shown only for L. quadrilineatus, and as a consequence the mean larval dispersal distance based on the isolation-by-distance model was estimated to be between 0.44 and 5 km. Estimates of the effective population size were the highest (1) in Hodeidah (southern Red Sea) for both L. quadrilineatus and C. viridis; and (2) in Tor (northern Red Sea) for P. squamipinnis. The results in this thesis were discussed in relation to the oceanographic factors and the biological features of the studied fishes. The historical event Last Glacial Maximum proved its influence on the population demographic history and the currents effective population size of the studied species. In order to enable a sustainable ornamental fishery on the studied species in the Red Sea, the results of this thesis suggest that (1) populations in the Red Sea should be managed as one stock for C. viridis; (2) populations of L. quadrilineatus northern and southern Red Sea should be managed as two stocks; and (3) populations in the Gulf of Aqaba and in the Red Sea proper should be managed separately for P. squamipinnis. The rather low larval dispersal distance of about 5 km needs to be considered in the design of MPAs to enable connectivity and self-seeding in L. quadrilineatus.

Published
2007

30. Genetic population structure, gene flow, and evolutionary history of selected ornamental fish in the Red Sea

Author

Froukh, Tawfiq and Froukh, Tawfiq

Abstract

The ornamental fishery is expanding rapidly in the Red Sea, and concerns about the possibility of overexploitation were raised. Marine protected areas (MPAs) were addressed as a potential solution to prevent overexploitation. However, the sources of stock recruitment are not well understood. This thesis aims to reveal the genetic population structure and the demographic connectivity in the endemic fish species of the Red Sea Larabicus quadrilineatus, and in the two common fish species Chromis viridis and Pseudanthias squamipinnis. The fish samples were obtained from five locations in the Red Sea. For comparison, additional samples of the two common species were obtained from two locations in the Indo-Malay Archipelago. Partial sequence of the mitochondrial control region was used as a molecular marker in the three studied species. The studied species exhibited high genetic diversity as inferred from the haplotype and nucleotide indices. Analysis of molecular variance (AMOVA) detected significant genetic variation between northern and central/southern populations of L. quadrilineatus (ΦCT = 0.01; P < 0.01), and between the populations in the Gulf of Aqaba and the Red Sea proper of P. squamipinnis (ΦST = 0.02; P < 0.01). In addition, AMOVA detected significant genetic variation between the Red Sea and the Indo-Malay Archipelago for both C. viridis (ΦCT = 0.462; P < 0.001) and P. squamipinnis (ΦST = 0.78; P < 0.001). Migration analysis in the Red Sea revealed (1) higher migration into the Gulf of Aqaba for all species; (2) higher northward migration for C. viridis and L. quadrilineatus; and higher southward migration in the Red Sea proper for P. squamipinnis. A significant relationship between the genetic versus the geographic distances was shown only for L. quadrilineatus, and as a consequence the mean larval dispersal distance based on the isolation-by-distance model was estimated to be between 0.44 and 5 km. Estimates of the effective population

31. PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality by disrupting mitochondrial pathways.

Author

Magrinelli F, Tesson C, Angelova PR, Salazar-Villacorta A, Rodriguez JA, Scardamaglia A, Chung BH, Jaconelli M, Vona B, Esteras N, Kwong AK, Courtin T, Maroofian R, Alavi S, Nirujogi R, Severino M, Lewis PA, Efthymiou S, O'Callaghan B, Buchert R, Sofan L, Lis P, Pinon C, Breedveld GJ, Chui MM, Murphy D, Pitz V, Makarious MB, Cassar M, Hassan BA, Iftikhar S, Rocca C, Bauer P, Tinazzi M, Svetel M, Samanci B, Hanağası HA, Bilgiç B, Obeso JA, Kurtis MM, Cogan G, Başak AN, Kiziltan G, Gül T, Yalçın G, Elibol B, Barišić N, Ng EW, Fan SS, Hershkovitz T, Weiss K, Raza Alvi J, Sultan T, Azmi Alkhawaja I, Froukh T, E Alrukban HA, Fauth C, Schatz UA, Zöggeler T, Zech M, Stals K, Varghese V, Gandhi S, Blauwendraat C, Hardy JA, Lesage S, Bonifati V, Haack TB, Bertoli-Avella AM, Steinfeld R, Alessi DR, Steller H, Brice A, Abramov AY, Bhatia KP, and Houlden H

Abstract

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.

Published
2024
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32. Loss of symmetric cell division of apical neural progenitors drives DENND5A -related developmental and epileptic encephalopathy.

Author

Banks E, Francis V, Lin SJ, Kharfallah F, Fonov V, Levesque M, Han C, Kulasekaran G, Tuznik M, Bayati A, Al-Khater R, Alkuraya FS, Argyriou L, Babaei M, Bahlo M, Bakhshoodeh B, Barr E, Bartik L, Bassiony M, Bertrand M, Braun D, Buchert R, Budetta M, Cadieux-Dion M, Calame D, Cope H, Cushing D, Efthymiou S, Elmaksoud MA, El Said HG, Froukh T, Gill HK, Gleeson JG, Gogoll L, Goh ES, Gowda VK, Haack TB, Hashem MO, Hauser S, Hoffman TL, Hogue JS, Hosokawa A, Houlden H, Huang K, Huynh S, Karimiani EG, Kaulfuß S, Korenke GC, Kritzer A, Lee H, Lupski JR, Marco EJ, McWalter K, Minassian A, Minassian BA, Murphy D, Neira-Fresneda J, Northrup H, Nyaga D, Oehl-Jaschkowitz B, Osmond M, Person R, Pehlivan D, Petree C, Sadleir LG, Saunders C, Schoels L, Shashi V, Spillman RC, Srinivasan VM, Torbati PN, Tos T, Zaki MS, Zhou D, Zweier C, Trempe JF, Durcan TM, Gan-Or Z, Avoli M, Alves C, Varshney GK, Maroofian R, Rudko DA, and McPherson PS

Abstract

Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A -related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families., Competing Interests: Competing Interests KM and RP are employed by GeneDx, LLC. All other authors report no conflicts of interest.

Published
2024
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