44 results on '"Silhavy JL"'
Search Results
2. A single human ciliopathy locus highlights the evolutionary dynamics of non-duplicated but adjacent genes
- Author
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Lee, Jh, Silhavy, Jl, Lee, Je, Al Gazali, L, Thomas, S, Davis, Ee, Bielas, Sl, Hill, Kj, Gabriel, Sb, Brancati, F, Iannicelli, M, Russ, C, Logan, Cv, Sharif, Sm, Bennett, Cp, Abe, M, Hildebrandt, F, Diplas, Bh, Attié Bitach, T, Katsanis, N, Rajab, A, Koul, R, Sztriha, L, Waters, E, Ferro Novick, S, Woods, Gc, Johnson, Ca, Valente, Enza Maria, Zaki, Ms, and Gleeson, J. G.
- Published
- 2012
3. TSGA14 is mutated in Joubert syndrome ans is required for tubulin glutamylation at the cilium
- Author
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Lee, Je, Silhavy, Jl, Zaki, Ms, Schroth, J, Bielas, Sl, Marsh, Se, Olvera, J, Brancati, F, Iannicelli, M, Ikegami, K, Schlossman, Am, Merriman, B, Attié Bitach, T, Logan, Cv, Glass, Ia, Cluckey, A, Louie, Cm, Lee, Jh, Raynes, Hr, Rapin, I, Setou, M, Barbot, C, Boltshauser, E, Nelson, Sf, Hildebrandt, F, Johnson, Ca, Doherty, Da, Valente, Enza Maria, and Gleeson, Jg
- Published
- 2012
4. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders
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Brancati F, Travaglini L, Zablocka D, Boltshauser E, Accorsi P, Montagna G, Silhavy JL, Barrano G, Bertini E, Emma F, Rigoli L and International JSRD Study Group, Leventer R, Grattan-Smith P, Janecke A, D'Hooghe M, Van Coster R, Dias K, Moco C, Moreira A, Ki
- Abstract
Joubert syndrome-related disorders (JSRDs) are autosomal recessive pleiotropic conditions sharing a peculiar cerebellar and brainstem malformation known as the 'molar tooth sign' (MTS). Recently, mutations in a novel ciliary gene, RPGRIP1L, have been shown to cause both JSRDs and Meckel-Gruber syndrome. We searched for RPGRIP1L mutations in 120 patients with proven MTS and phenotypes representative of all JSRD clinical subgroups. Two homozygous mutations, the previously reported p.T615P in exon 15 and the novel c.2268_2269delA in exon 16, were detected in 2 of 16 families with cerebello-renal presentation ( approximately 12%). Conversely, no pathogenic changes were found in patients with other JSRD phenotypes, suggesting that RPGRIP1L mutations are largely confined to the cerebello-renal subgroup, while they overall represent a rare cause of JSRD (
- Published
- 2008
5. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders
- Author
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Brancati, F, Travaglini, L, Zablocka, D, Boltshauser, E, Accorsi, P, Montagna, G, Silhavy, Jl, Barrano, G, Bertini, E, Emma, F, Rigoli, L, Dallapiccola, B, Gleeson, Jg, and Valente, Em
- Published
- 2008
6. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome
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Cantagrel, V, Silhavy, Jl, Bielas, S, Swistun, D, Marsh, Se, Bertrand, J, Audollent, S, Attié Bitach, T, Holden, Kr, Dobyns, Wb, Traver, D, Al Gazali, L, Ali, Br, Lindner, Th, Caspary, T, Otto, Ea, Hildebrandt, F, Glass, Ia, Logan, Cv, Johnson, Ca, Bennett, C, Brancati, F, Grattan Smith, P, Leventer, J, Van Coster, R, Dias, K, Moco, C, Moreira, Ae Kim, C, Akiss, A, Maegawa, G, Abdel Salam GMH, Abdel Aleem, A, Zaki, Ms, Marti, I, Quijano Roy, S, de Lonlay, P, Verloes A, A., Touraine, R, Koenig, M, Lagier Tourenne, C, Messer, J, Philippi, H, Tzeli, Sk, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Magee, A, Stuart, B, Lev, D, Michelson, M, Ben Zeev, B, Fischetto, R, Gentile, M, Battaglia, Giordano, L, Boccone, L, Ruggieri, M, Bigoni, S, Ferlini, A, Donati, Ma, Procopio, E, Lapi, E, Genuardi, M, Caridi, G, Faravelli, F, Ghiggeri, G, Briuglia, Silvana, Tortorella, Gaetano, Rigoli, Luciana Concetta, SALPIETRO DAMIANO, Carmelo, D’Arrigo, S, Pantaleoni, C, Riva, D, Uziel, G, Laverda, Am, Permunian, A, Bova, S, Fazz, Ei, Sabrina, S, Battini, R, Bertini, E, Dallapiccola, B, Cilio, Mr, Di Sabato, M, Emma, F, Leuzzi, V, Parisi, P, Simonati, A, Al Tawari AA, Bastaki, L, Ahmad Aqueel, A, Jong, Mm, Koul, R, Rajab, A, Sztriha, L, Azam, M, Barbot, C, Rodriguez, B, Pascual Castroviejo, I, Eugen Boltshauser, E, Hulya, H, Comu, S, Akcakus, M, Sahin, Y, Phadke, Sr, Melick, N, Mikati, M, Nicholl, D, Hurst, J, Hennekam, Rcm, Bernes, S, Sanchez, H, Clark, Ae, Wynshaw Boris, A, Donahue, C, Sherr, Eh, Barkovich, Aj, Hahn, D., Sanger, Td, Gallager, Te, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Walsh CA, Soul, Jmckanna, T, Joanne Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Amy Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Cruse, Rp, Lotzete, Swoboda, Kj, Viskochil, Dh, Valente, Em, Woods, Cg, and Gleeson, Jg
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Cerebellum ,Ataxia ,TMEM67 ,Molecular Sequence Data ,Biology ,Joubert Syndrome ,Joubert syndrome ,Article ,cilia gene ARL13B ,mutation ,03 medical and health sciences ,0302 clinical medicine ,Ciliogenesis ,INPP5E ,medicine ,Genetics ,Animals ,Humans ,Genetics(clinical) ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Cilia ,Genetics (clinical) ,Conserved Sequence ,Zebrafish ,030304 developmental biology ,Neurons ,0303 health sciences ,Brain Diseases ,ADP-Ribosylation Factors ,Cilium ,Chromosome Mapping ,Computational Biology ,Syndrome ,Mutation ,medicine.disease ,Cell biology ,medicine.anatomical_structure ,RPGRIP1L ,medicine.symptom ,Abnormalities ,Multiple ,030217 neurology & neurosurgery - Abstract
Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the “molar tooth sign” on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.
- Published
- 2008
7. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders
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Brancati, F, Barrano, G, Silhavy, Jl, Marsh, Se, Travaglini, L, Bielas, Sl, Amorini, M, Zablocka, D, Kayserili, H, Al Gazali, L, Bertini, E, Boltshauser, E, D'Hooghe, M, Fazzi, E, Fenerci, Ey, Hennekam, Rc, Kiss, A, Lees, Mm, Marco, E, Phadke, Sr, Rigoli, L, Romano, S, Salpietro, Cd, Sherr, Eh, Signorini, S, Stromme, P, Stuart, B, Sztriha, L, Viskochil, Dh, Yuksel, A, Dallapiccola, [International JSRD Study Group], Valente, Em, Gleeson, Jg, Smith, P, Leventer, R, Janecke, A, Van Coster, R, Dias, K, Moco, C, Moreira, A, Chong, Ak, Maegawa, G, Abdel Salam GMH, Abdel Aleem, A, Zaki, Ms, Martu, I, Quijano Roy, S, De Lonlay, P, Verloes, A, Touraine, R, Koenig, M, Lagier Tourenne, C, Messer, J, Philippi, H, Tzeli, Sk, Halldorsson, S, Johannsdotir, J, Ludvigsson, P, Magee, A, Lev, D, Michelson, M, Ben Zev, B, Fischetto, R, Gentile, M, Battaglia, S, Giordano, L, Boccone, L, Ruggieri, Martino, Bigoni, S, Ferlini, A, Donati, Ma, Procopio, E, Cardidi, G, Faravelli, F, Ghiggeri, G, Briuglia, S, Tortorella, G, D’Arrigo, S, Pantaleoni, C, Riva, D, Uziel, G, Lavercla, Am, Permunian, A, Bova, S, Battini, R, Cilio, Mr, Di Sabato, M, Emma, F, Leuzzi, V, Parisi, P, Simonati, A, Al Tawari AA, Bastaki, L, Aqeel, A, De Jong MM, Koul, R, Rajab, A, Azam, M, Barbot, C, Rodriguez, B, Pascual Castroviejo, I, Comu, S, Akcakus, M, Nicholl, D, Woods, Cg, Bennet, C, Hurst, J, Walsh, Ca, Bernes, S, Sanchez, H, Clark, Ae, Donahue, C, Hahn, J, Sanger, Td, Gallager, Te, Dobyns, Wb, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Mckanna, T, Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Holden, K, Cruse, Rp, and Swoboda, Kj
- Published
- 2007
8. AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders
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Valente, Em, Brancati, F, Silhavy, Jl, Castori, M, Marsh, Se, Barrano, G, Bertini, E, Boltshauser, E, Zaki, Ms, Abdel Aleem, A, Abdel Salam GM, Bellacchio, E, Battini, R, Cruse, Rp, Dobyns, Wb, Krishnamoorthy, Ks, Lagier Tourenne, C, Magee, A, Pascual Castroviejo, I, SALPIETRO DAMIANO, Carmelo, Sarco, D, Richard, Leventer, Padraic Grattan Smith, Andreas, Janecke, Marc, D’Hooghe, Rudy Van Coster, Karin, Dias, Carla, Moco, Ana, Moreira, Chong Ae Kim, Gustavo, Maegawa, Itxaso, Marti, Susana Quijano Roy, Alain, Verloes, Renaud, Touraine, Miche, Bernard, Stuart, Dorit, Lev, Bruria Ben Zeev, Rita, Fischetto, Mattia, Gentile, Lucio, Giordano, Loredana, Boccone, Martino, Ruggieri, Stefania, Bigoni, Maria Alide Donati, Elena, Procopio, Gianluca, Caridi, Francesca, Faravelli, Gianmarco, Ghiggeri, Briuglia, Silvana, Gaetano, Tortorella, Stefano, D’Arrigo, Chiara, Pantaleoni, Daria, Riva, Graziella, Uziel, Stefania, Bova, Elisa, Fazzi, Sabrina, Signorini, Maria Roberta Cilio, Marilu` Di Sabato, Francesco, Emma, Vincenzo, Leuzzi, Pasquale, Parisi, Alessandro, Simonati, de Jong, Mirjam M., Matloob, Azam, Berta, Rodriguez, Hulya, Kayserili, Lihadh Al Gazali, Laszlo, Sztriha, David, Nicholl, Geoffrey Woods, C., Raoul, Hennekam, Saunder, Bernes, Henry, Sanchez, Clark, Aldon E., Elysa, Demarco, Clement, Donahue, Elliot, Sherr, Jin, Hahn, Terence, D, Sanger, Gallager H, Tomas E., Cynthia, Daugherty, Walsh, Christopher A., Trudy, Mckanna, Joanne, Milisa, Chung, Wendy K., De Vivo, Darryl C., Hillary, Raynes, Romaine, Schubert, Alison, Seward, Brooks, David G., Amy, Goldstein, James, Caldwell, Eco, Finsecke, Kenton, Holden, Swobod, Kathryn J., Dave Viskochil, Dallapiccola, B, and Gleeson, Jg
- Subjects
Male ,Models, Molecular ,Developmental Disabilities ,DNA Mutational Analysis ,Chromosome Disorders ,Gene mutation ,medicine.disease_cause ,Gene Frequency ,Models ,Missense mutation ,Adaptor Proteins, Signal Transducing ,Adolescent ,Adult ,Animals ,Brain Diseases ,Brain Stem ,Child ,Child, Preschool ,Family Health ,Female ,Humans ,Infant ,Magnetic Resonance Imaging ,Polymorphism, Genetic ,Mutation ,Neuroscience (all) ,Genetics ,Adaptor Proteins ,Joubert syndrome ,Joubert Syndrome Related Disorders ,AHI1 gene ,mutation ,Neurology ,Consanguinity ,Biology ,Genetic ,medicine ,Polymorphism ,Preschool ,Gene ,Allele frequency ,Signal Transducing ,Molecular ,medicine.disease ,Adaptor Proteins, Vesicular Transport ,Cerebellar vermis ,Neurology (clinical) - Abstract
Author(s): Valente, E M; Brancat, F; Silhavy, J L; Castori, M; March, S E; Barrano, G; Bertini, E; Boltshauser, E; Zaki, M S; Abdel-Aleem, A; Abdel-Salam, GMH; Bellacchlo, E; Battini, R; Cruse, R P; Dobyns, W B; Krishnamoorthy, K S; Lagier-Tourenne, C; Magee, A; Pascual-Castroviejo, I; Salpietro, C D; Sarco, D; Dallapiccola, B; Gleeson, J G | Abstract: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. Methods: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. Results: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. Interpretation AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.
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- 2006
9. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome
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Valente, Enza Maria, Silhavy, Jl, Brancati, F, Barrano, G, Krishnaswami, Sr, Castori, M, Lancaster, Ma, Boltshauser, E, Boccone, L, AL GAZALI, L, Fazzi, E, Signorini, S, Louie, Cm, Bellacchio, E, Bertini, E, Dallapiccola, B, and Gleeson, Jg
- Published
- 2006
10. Mutations in the CEP290 gene, encoding a centrosomal protein, cause pleiotropic forms of Joubert Syndrome
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Valente, Em, Silhavy, Jl, Brancati, F., Barrano, G, Krishnaswami, Sr, Castori, M, Lancaster, Ma, Boltshauser, E, Boccone, L, AL-GAZALI, L, Fazzi, E, Signorini, S, Louie, Cm, Bellacchio, E, Bertini, E, DALLA PICCOLA, B, and Gleeson, Jg
- Published
- 2006
11. Mild paroxysmal kinesigenic dyskinesia caused by PRRT2 missense mutation with reduced penetrance.
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Friedman J, Olvera J, Silhavy JL, Gabriel SB, Gleeson JG, Friedman, Jennifer, Olvera, Jesus, Silhavy, Jennifer L, Gabriel, Stacey B, and Gleeson, Joseph G
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- 2012
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12. Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.
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Guemez-Gamboa A, Çağlayan AO, Stanley V, Gregor A, Zaki MS, Saleem SN, Musaev D, McEvoy-Venneri J, Belandres D, Akizu N, Silhavy JL, Schroth J, Rosti RO, Copeland B, Lewis SM, Fang R, Issa MY, Per H, Gumus H, Bayram AK, Kumandas S, Akgumus GT, Erson-Omay EZ, Yasuno K, Bilguvar K, Heimer G, Pillar N, Shomron N, Weissglas-Volkov D, Porat Y, Einhorn Y, Gabriel S, Ben-Zeev B, Gunel M, and Gleeson JG
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- Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Protocadherins, Brain Stem abnormalities, Cadherins genetics, Nervous System Malformations genetics, Nervous System Malformations pathology
- Abstract
Objective: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome., Methods: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression., Results: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth., Interpretation: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655., (© 2018 American Neurological Association.)
- Published
- 2018
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13. Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration.
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Schaffer AE, Breuss MW, Caglayan AO, Al-Sanaa N, Al-Abdulwahed HY, Kaymakçalan H, Yılmaz C, Zaki MS, Rosti RO, Copeland B, Baek ST, Musaev D, Scott EC, Ben-Omran T, Kariminejad A, Kayserili H, Mojahedi F, Kara M, Cai N, Silhavy JL, Elsharif S, Fenercioglu E, Barshop BA, Kara B, Wang R, Stanley V, James KN, Nachnani R, Kalur A, Megahed H, Incecik F, Danda S, Alanay Y, Faqeih E, Melikishvili G, Mansour L, Miller I, Sukhudyan B, Chelly J, Dobyns WB, Bilguvar K, Jamra RA, Gunel M, and Gleeson JG
- Subjects
- Actin-Related Protein 2-3 Complex metabolism, Animals, Cerebral Cortex metabolism, Cerebral Cortex pathology, Embryo, Mammalian, Genome, Human, Humans, Mice, Mice, Inbred C57BL, Mutation, Nerve Tissue Proteins genetics, Neurons metabolism, Pedigree, alpha Catenin metabolism, Actin-Related Protein 2-3 Complex genetics, Cell Movement genetics, Cerebral Cortex physiology, Neurons pathology, alpha Catenin genetics
- Abstract
Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between β-catenin and Arp2/3 actin filament activities
1 . Loss of αN-catenin did not affect β-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.- Published
- 2018
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14. A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features.
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Marin-Valencia I, Novarino G, Johansen A, Rosti B, Issa MY, Musaev D, Bhat G, Scott E, Silhavy JL, Stanley V, Rosti RO, Gleeson JW, Imam FB, Zaki MS, and Gleeson JG
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- Animals, Autistic Disorder complications, Epilepsy complications, Homozygote, Humans, Microcephaly complications, Phenotype, Zebrafish, Autistic Disorder genetics, Epilepsy genetics, Founder Effect, Genetic Association Studies, Microcephaly genetics, Mutation genetics, Neurodevelopmental Disorders genetics, Vesicular Transport Proteins genetics
- Abstract
Background: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain., Objective: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families., Methods: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease., Results: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B , encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold., Conclusion: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
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- 2018
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15. Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome.
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Rosti RO, Sotak BN, Bielas SL, Bhat G, Silhavy JL, Aslanger AD, Altunoglu U, Bilge I, Tasdemir M, Yzaguirrem AD, Musaev D, Infante S, Thuong W, Marin-Valencia I, Nelson SF, Kayserili H, and Gleeson JG
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- Adolescent, Child, Developmental Disabilities genetics, Female, Homozygote, Humans, Infant, Kidney metabolism, Male, Pedigree, Phenotype, Proteins genetics, Turkey, Hernia, Hiatal genetics, Microcephaly genetics, Mutation genetics, Nephrosis genetics, Nephrotic Syndrome genetics, Nuclear Pore Complex Proteins genetics, Steroids metabolism
- Abstract
Background: Microcephaly with nephrotic syndrome is a rare co-occurrence, constituting the Galloway-Mowat syndrome (GAMOS), caused by mutations in WDR73 (OMIM: 616144). However, not all patients harbour demonstrable WDR73 deleterious variants, suggesting that there are other yet unidentified factors contributing to GAMOS aetiology., Methods: Autozygosity mapping and candidate analysis was used to identify deleterious variants in consanguineous families. Analysis of patient fibroblasts was used to study splicing and alterations in cellular function., Results: In two consanguineous families with five affected individuals from Turkey with a GAMOS-like presentation, we identified a shared homozygous variant leading to partial exon 4 skipping in nucleoporin, 107-KD ( NUP107 ). The founder mutation was associated with concomitant reduction in NUP107 protein and in the obligate binding partner NUP133 protein, as well as density of nuclear pores in patient cells., Conclusion: Recently, NUP107 was suggested as a candidate in a family with nephrotic syndrome and developmental delay. Other NUP107 -reported cases had isolated renal phenotypes. With the addition of these individuals, we implicate an allele-specific critical role for NUP107 in the regulation of brain growth and a GAMOS-like presentation., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2017
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16. Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features.
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Santiago-Sim T, Burrage LC, Ebstein F, Tokita MJ, Miller M, Bi W, Braxton AA, Rosenfeld JA, Shahrour M, Lehmann A, Cogné B, Küry S, Besnard T, Isidor B, Bézieau S, Hazart I, Nagakura H, Immken LL, Littlejohn RO, Roeder E, Kara B, Hardies K, Weckhuysen S, May P, Lemke JR, Elpeleg O, Abu-Libdeh B, James KN, Silhavy JL, Issa MY, Zaki MS, Gleeson JG, Seavitt JR, Dickinson ME, Ljungberg MC, Wells S, Johnson SJ, Teboul L, Eng CM, Yang Y, Kloetzel PM, Heaney JD, and Walkiewicz MA
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- Adolescent, Animals, Child, Child, Preschool, Disease Models, Animal, Female, Gene Deletion, Humans, Male, Mice, Pedigree, Proteasome Endopeptidase Complex genetics, Proteasome Endopeptidase Complex metabolism, Seizures genetics, Abnormalities, Multiple genetics, Endopeptidases genetics, Intellectual Disability genetics
- Abstract
Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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17. Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.
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Lardelli RM, Schaffer AE, Eggens VR, Zaki MS, Grainger S, Sathe S, Van Nostrand EL, Schlachetzki Z, Rosti B, Akizu N, Scott E, Silhavy JL, Heckman LD, Rosti RO, Dikoglu E, Gregor A, Guemez-Gamboa A, Musaev D, Mande R, Widjaja A, Shaw TL, Markmiller S, Marin-Valencia I, Davies JH, de Meirleir L, Kayserili H, Altunoglu U, Freckmann ML, Warwick L, Chitayat D, Blaser S, Çağlayan AO, Bilguvar K, Per H, Fagerberg C, Christesen HT, Kibaek M, Aldinger KA, Manchester D, Matsumoto N, Muramatsu K, Saitsu H, Shiina M, Ogata K, Foulds N, Dobyns WB, Chi NC, Traver D, Spaccini L, Bova SM, Gabriel SB, Gunel M, Valente EM, Nassogne MC, Bennett EJ, Yeo GW, Baas F, Lykke-Andersen J, and Gleeson JG
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- Alleles, Animals, Female, Humans, Male, Mice, Neurodegenerative Diseases genetics, RNA, Messenger genetics, Spliceosomes genetics, Zebrafish, Cerebellar Diseases genetics, Exonucleases genetics, Mutation genetics, Nuclear Proteins genetics, RNA, Small Nuclear genetics
- Abstract
Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg
2+ -dependent 3'-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3' genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3'-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3'-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3' ends.- Published
- 2017
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18. Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly.
- Author
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Jerber J, Zaki MS, Al-Aama JY, Rosti RO, Ben-Omran T, Dikoglu E, Silhavy JL, Caglar C, Musaev D, Albrecht B, Campbell KP, Willer T, Almuriekhi M, Çağlayan AO, Vajsar J, Bilgüvar K, Ogur G, Abou Jamra R, Günel M, and Gleeson JG
- Subjects
- Amino Acid Sequence, Basement Membrane metabolism, Brain abnormalities, Brain diagnostic imaging, Carrier Proteins metabolism, Cerebellum abnormalities, Cerebellum diagnostic imaging, Cobblestone Lissencephaly diagnostic imaging, Developmental Disabilities diagnostic imaging, Developmental Disabilities genetics, Dystroglycans metabolism, Eye Abnormalities diagnostic imaging, Eye Abnormalities genetics, Female, Humans, Infant, Male, Membrane Proteins metabolism, Mutation, Nervous System Malformations diagnostic imaging, Nervous System Malformations genetics, Neuroglia metabolism, Neurons pathology, Pedigree, Phenotype, Alleles, Carrier Proteins genetics, Cobblestone Lissencephaly genetics, Membrane Proteins genetics
- Abstract
Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement., (Copyright © 2016. Published by Elsevier Inc.)
- Published
- 2016
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19. Identification of a homozygous nonsense mutation in KIAA0556 in a consanguineous family displaying Joubert syndrome.
- Author
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Roosing S, Rosti RO, Rosti B, de Vrieze E, Silhavy JL, van Wijk E, Wakeling E, and Gleeson JG
- Subjects
- Abnormalities, Multiple physiopathology, Adult, Animals, Cerebellum physiopathology, Child, Child, Preschool, Cilia drug effects, Cilia pathology, Ciliopathies physiopathology, DNA, Complementary administration & dosage, Disease Models, Animal, Exome genetics, Eye Abnormalities physiopathology, Female, Gene Knockdown Techniques, Homozygote, Humans, Kidney Diseases, Cystic physiopathology, Male, Pedigree, Phenotype, Retina physiopathology, Zebrafish genetics, Abnormalities, Multiple genetics, Cerebellum abnormalities, Ciliopathies genetics, Codon, Nonsense genetics, Eye Abnormalities genetics, Kidney Diseases, Cystic genetics, Microtubule-Associated Proteins genetics, Retina abnormalities
- Abstract
Joubert Syndrome (JS) is an inherited ciliopathy associated with mutations in genes essential in primary cilium function. Whole exome sequencing in a multiplex consanguineous family from India revealed a KIAA0556 homozygous single base pair deletion mutation (c.4420del; p.Met1474Cysfs*11). Knockdown of the gene in zebrafish resulted in a ciliopathy phenotype, rescued by co-injection of wildtype cDNA. Affected siblings present a mild and classical form of Joubert syndrome allowing for further delineation of the JS associated genotypic spectrum.
- Published
- 2016
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20. Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome.
- Author
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Roosing S, Hofree M, Kim S, Scott E, Copeland B, Romani M, Silhavy JL, Rosti RO, Schroth J, Mazza T, Miccinilli E, Zaki MS, Swoboda KJ, Milisa-Drautz J, Dobyns WB, Mikati MA, İncecik F, Azam M, Borgatti R, Romaniello R, Boustany RM, Clericuzio CL, D'Arrigo S, Strømme P, Boltshauser E, Stanzial F, Mirabelli-Badenier M, Moroni I, Bertini E, Emma F, Steinlin M, Hildebrandt F, Johnson CA, Freilinger M, Vaux KK, Gabriel SB, Aza-Blanc P, Heynen-Genel S, Ideker T, Dynlacht BD, Lee JE, Valente EM, Kim J, and Gleeson JG
- Subjects
- Abnormalities, Multiple genetics, Eye Abnormalities genetics, Gene Frequency, Genetic Testing, Genome-Wide Association Study, Heterozygote, Humans, Kidney Diseases, Cystic genetics, RNA, Small Interfering genetics, Cell Cycle Proteins genetics, Cerebellum abnormalities, Genetic Predisposition to Disease, Mutant Proteins genetics, Retina abnormalities
- Abstract
Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.
- Published
- 2015
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21. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.
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Akizu N, Cantagrel V, Zaki MS, Al-Gazali L, Wang X, Rosti RO, Dikoglu E, Gelot AB, Rosti B, Vaux KK, Scott EM, Silhavy JL, Schroth J, Copeland B, Schaffer AE, Gordts PL, Esko JD, Buschman MD, Field SJ, Napolitano G, Abdel-Salam GM, Ozgul RK, Sagıroglu MS, Azam M, Ismail S, Aglan M, Selim L, Mahmoud IG, Abdel-Hadi S, Badawy AE, Sadek AA, Mojahedi F, Kayserili H, Masri A, Bastaki L, Temtamy S, Müller U, Desguerre I, Casanova JL, Dursun A, Gunel M, Gabriel SB, de Lonlay P, and Gleeson JG
- Subjects
- Animals, Atrophy genetics, Autophagy, Child, Preschool, Female, Gene Frequency, Humans, Infant, Lod Score, Lysosomal Storage Diseases genetics, Male, Mutation, Syndrome, Zebrafish, Cerebellar Diseases genetics, Cerebellum pathology, Lysosomes metabolism, Phagosomes metabolism, Sorting Nexins genetics, Spinocerebellar Ataxias genetics
- Abstract
Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.
- Published
- 2015
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22. CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.
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Schaffer AE, Eggens VR, Caglayan AO, Reuter MS, Scott E, Coufal NG, Silhavy JL, Xue Y, Kayserili H, Yasuno K, Rosti RO, Abdellateef M, Caglar C, Kasher PR, Cazemier JL, Weterman MA, Cantagrel V, Cai N, Zweier C, Altunoglu U, Satkin NB, Aktar F, Tuysuz B, Yalcinkaya C, Caksen H, Bilguvar K, Fu XD, Trotta CR, Gabriel S, Reis A, Gunel M, Baas F, and Gleeson JG
- Subjects
- Animals, Brain metabolism, Brain pathology, Cleavage And Polyadenylation Specificity Factor genetics, Female, Humans, Male, Mice, Models, Molecular, Neurodegenerative Diseases genetics, Neurodegenerative Diseases pathology, Nuclear Proteins metabolism, Pedigree, Phosphotransferases metabolism, RNA, Transfer metabolism, Saccharomyces cerevisiae metabolism, Transcription Factors metabolism, Zebrafish, Zebrafish Proteins genetics, Cerebellum growth & development, Cerebellum pathology, Cleavage And Polyadenylation Specificity Factor metabolism, Nuclear Proteins genetics, Phosphotransferases genetics, RNA Splicing, RNA, Transfer genetics, Transcription Factors genetics, Zebrafish Proteins metabolism
- Abstract
Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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23. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.
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Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GMH, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, El Din Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, and Gleeson JG
- Subjects
- Animals, Axons physiology, Biological Transport genetics, Cohort Studies, Gene Regulatory Networks, Humans, Mutation, Nucleotides genetics, Nucleotides metabolism, Sequence Analysis, DNA, Synapses physiology, Transcriptome, Zebrafish, Exome genetics, Genetic Association Studies, Motor Neuron Disease genetics, Neurons metabolism, Pyramidal Tracts metabolism, Spastic Paraplegia, Hereditary genetics
- Abstract
Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.
- Published
- 2014
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24. Mutations in CSPP1 lead to classical Joubert syndrome.
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Akizu N, Silhavy JL, Rosti RO, Scott E, Fenstermaker AG, Schroth J, Zaki MS, Sanchez H, Gupta N, Kabra M, Kara M, Ben-Omran T, Rosti B, Guemez-Gamboa A, Spencer E, Pan R, Cai N, Abdellateef M, Gabriel S, Halbritter J, Hildebrandt F, van Bokhoven H, Gunel M, and Gleeson JG
- Subjects
- Abnormalities, Multiple, Brain pathology, Cell Cycle Proteins metabolism, Centrosome metabolism, Cerebellum abnormalities, Cilia genetics, Cilia pathology, Cohort Studies, Fibroblasts cytology, Fibroblasts metabolism, Humans, Image Processing, Computer-Assisted, Microtubule-Associated Proteins metabolism, Polymorphism, Single Nucleotide, Cell Cycle Proteins genetics, Cerebellar Diseases genetics, Eye Abnormalities genetics, Gene Deletion, Kidney Diseases, Cystic genetics, Microtubule-Associated Proteins genetics, Retina abnormalities
- Abstract
Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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25. AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.
- Author
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Akizu N, Cantagrel V, Schroth J, Cai N, Vaux K, McCloskey D, Naviaux RK, Van Vleet J, Fenstermaker AG, Silhavy JL, Scheliga JS, Toyama K, Morisaki H, Sonmez FM, Celep F, Oraby A, Zaki MS, Al-Baradie R, Faqeih EA, Saleh MA, Spencer E, Rosti RO, Scott E, Nickerson E, Gabriel S, Morisaki T, Holmes EW, and Gleeson JG
- Subjects
- AMP Deaminase chemistry, AMP Deaminase genetics, Animals, Brain Stem pathology, Cerebellum pathology, Child, Female, Guanosine Triphosphate metabolism, Humans, Male, Mice, Mice, Knockout, Mutation, Neural Stem Cells metabolism, Olivopontocerebellar Atrophies genetics, Olivopontocerebellar Atrophies pathology, Protein Biosynthesis, Saccharomyces cerevisiae enzymology, Saccharomyces cerevisiae metabolism, AMP Deaminase metabolism, Olivopontocerebellar Atrophies metabolism, Purines biosynthesis
- Abstract
Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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26. Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities.
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Radmanesh F, Caglayan AO, Silhavy JL, Yilmaz C, Cantagrel V, Omar T, Rosti B, Kaymakcalan H, Gabriel S, Li M, Sestan N, Bilguvar K, Dobyns WB, Zaki MS, Gunel M, and Gleeson JG
- Subjects
- Basement Membrane metabolism, Basement Membrane pathology, Brain metabolism, Brain pathology, Cerebellum metabolism, Cerebellum pathology, Cerebral Cortex metabolism, Cerebral Cortex pathology, Encephalocele genetics, Encephalocele metabolism, Encephalocele pathology, Female, Genetic Predisposition to Disease, Homozygote, Humans, Male, Muscular Dystrophies metabolism, Muscular Dystrophies pathology, Nervous System Malformations metabolism, Nervous System Malformations pathology, Neuroglia metabolism, Neuroglia pathology, Neurons metabolism, Neurons pathology, Walker-Warburg Syndrome metabolism, Walker-Warburg Syndrome pathology, Brain abnormalities, Laminin genetics, Muscular Dystrophies genetics, Nervous System Malformations genetics, Sequence Deletion, Walker-Warburg Syndrome genetics
- Abstract
Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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27. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.
- Author
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Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA, State MW, and Gleeson JG
- Subjects
- 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) deficiency, Adolescent, Amino Acids, Branched-Chain administration & dosage, Amino Acids, Branched-Chain blood, Amino Acids, Branched-Chain deficiency, Animals, Arginine genetics, Autistic Disorder enzymology, Base Sequence, Brain metabolism, Child, Child, Preschool, Diet, Epilepsy enzymology, Female, Homozygote, Humans, Intellectual Disability diet therapy, Intellectual Disability enzymology, Intellectual Disability genetics, Male, Mice, Mice, Knockout, Molecular Sequence Data, Mutation, Pedigree, Phosphorylation, Protein Folding, Protein Structure, Tertiary, RNA, Messenger metabolism, Young Adult, 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) administration & dosage, 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) genetics, Autistic Disorder diet therapy, Autistic Disorder genetics, Epilepsy diet therapy, Epilepsy genetics
- Abstract
Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.
- Published
- 2012
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28. A missense founder mutation in VLDLR is associated with Dysequilibrium Syndrome without quadrupedal locomotion.
- Author
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Ali BR, Silhavy JL, Gleeson MJ, Gleeson JG, and Al-Gazali L
- Subjects
- Adolescent, Brain diagnostic imaging, Child, Child, Preschool, Female, Haplotypes, Homozygote, Humans, Magnetic Resonance Imaging, Male, Mutation, Missense, Pedigree, Phenotype, Protein Structure, Tertiary, Radionuclide Imaging, Sequence Analysis, DNA, Cerebellar Ataxia genetics, Intellectual Disability genetics, Locomotion genetics, Receptors, LDL genetics
- Abstract
Background: Dysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. The condition has been classified into cerebellar ataxia, mental retardation and disequilibrium syndrome types 1 (CAMRQ1), 2 (CAMRQ2) and 3 (CAMRQ3) and attributed to mutations in VLDLR, CA8 and WDR81 genes, respectively. Quadrupedal locomotion in this syndrome has been reported in association with mutations in all three genes., Methods: SNP mapping and candidate gene sequencing in one consanguineous Omani family from the United Arab Emirates with cerebellar hypoplasia, moderate mental retardation, delayed ambulation and truncal ataxia was used to identify the mutation. In a second unrelated consanguineous Omani family, massively parallel exonic sequencing was used., Results: We identified a homozygous missense mutation (c.2117 G > T, p.C706F) in the VLDLR gene in both families on a shared affected haplotype block.This is the first reported homozygous missense mutation in VLDLR and it occurs in a highly conserved residue and predicted to be damaging to protein function., Conclusions: We have delineated the phenotype associated with dysequilibrium syndrome in two Omani families and identified the first homozygous missense pathogenic mutation in VLDLR gene with likely founder effect in the southeastern part of the Arabian Peninsula.
- Published
- 2012
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29. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.
- Author
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Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T, Heiberg A, Scott E, Bafna V, Hill KJ, Collazo A, Funari V, Russ C, Gabriel SB, Mathern GW, and Gleeson JG
- Subjects
- Child, Preschool, Class I Phosphatidylinositol 3-Kinases, DNA Mutational Analysis, Exome, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Malformations of Cortical Development metabolism, Malformations of Cortical Development pathology, Mosaicism, Signal Transduction genetics, Malformations of Cortical Development genetics, Mutation, Missense, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins c-akt genetics, TOR Serine-Threonine Kinases genetics
- Abstract
De novo somatic mutations in focal areas are well documented in diseases such as neoplasia but are rarely reported in malformation of the developing brain. Hemimegalencephaly (HME) is characterized by overgrowth of either one of the two cerebral hemispheres. The molecular etiology of HME remains a mystery. The intractable epilepsy that is associated with HME can be relieved by the surgical treatment hemispherectomy, allowing sampling of diseased tissue. Exome sequencing and mass spectrometry analysis in paired brain-blood samples from individuals with HME (n = 20 cases) identified de novo somatic mutations in 30% of affected individuals in the PIK3CA, AKT3 and MTOR genes. A recurrent PIK3CA c.1633G>A mutation was found in four separate cases. Identified mutations were present in 8-40% of sequenced alleles in various brain regions and were associated with increased neuronal S6 protein phosphorylation in the brains of affected individuals, indicating aberrant activation of mammalian target of rapamycin (mTOR) signaling. Thus HME is probably a genetically mosaic disease caused by gain of function in phosphatidylinositol 3-kinase (PI3K)-AKT3-mTOR signaling.
- Published
- 2012
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30. Exome sequencing can improve diagnosis and alter patient management.
- Author
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Dixon-Salazar TJ, Silhavy JL, Udpa N, Schroth J, Bielas S, Schaffer AE, Olvera J, Bafna V, Zaki MS, Abdel-Salam GH, Mansour LA, Selim L, Abdel-Hadi S, Marzouki N, Ben-Omran T, Al-Saana NA, Sonmez FM, Celep F, Azam M, Hill KJ, Collazo A, Fenstermaker AG, Novarino G, Akizu N, Garimella KV, Sougnez C, Russ C, Gabriel SB, and Gleeson JG
- Subjects
- Female, Humans, Male, Mutation, Pedigree, Sequence Analysis, DNA, Vesicular Transport Proteins genetics, Exome genetics
- Abstract
The translation of "next-generation" sequencing directly to the clinic is still being assessed but has the potential for genetic diseases to reduce costs, advance accuracy, and point to unsuspected yet treatable conditions. To study its capability in the clinic, we performed whole-exome sequencing in 118 probands with a diagnosis of a pediatric-onset neurodevelopmental disease in which most known causes had been excluded. Twenty-two genes not previously identified as disease-causing were identified in this study (19% of cohort), further establishing exome sequencing as a useful tool for gene discovery. New genes identified included EXOC8 in Joubert syndrome and GFM2 in a patient with microcephaly, simplified gyral pattern, and insulin-dependent diabetes. Exome sequencing uncovered 10 probands (8% of cohort) with mutations in genes known to cause a disease different from the initial diagnosis. Upon further medical evaluation, these mutations were found to account for each proband's disease, leading to a change in diagnosis, some of which led to changes in patient management. Our data provide proof of principle that genomic strategies are useful in clarifying diagnosis in a proportion of patients with neurodevelopmental disorders.
- Published
- 2012
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31. A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance.
- Author
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Ali BR, Silhavy JL, Akawi NA, Gleeson JG, and Al-Gazali L
- Subjects
- Consanguinity, Humans, Magnetic Resonance Imaging, Phenotype, Abnormalities, Multiple genetics, Facies, Genes, Recessive, Kinesins genetics, Megalencephaly genetics, Mutation, Missense, Osteochondrodysplasias genetics
- Abstract
Background: We previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26., Methods: In this manuscript, we have used whole exome sequencing on two affected members of a consanguineous family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation., Results: Our analysis resulted in the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently found to be causing Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. The phenotype in our patients partially overlaps with the phenotypes associated with those syndromes but they also exhibit some distinctive features including multiple epiphyseal dysplasia., Conclusions: We report the first missense homozygous disease-causing mutation in KIF7 and expand the clinical spectrum associated with mutations in this gene to include multiple epiphyseal dysplasia. The missense nature of the mutation might account for the unique presentation in our patients.
- Published
- 2012
- Full Text
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32. Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.
- Author
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Lee JH, Silhavy JL, Lee JE, Al-Gazali L, Thomas S, Davis EE, Bielas SL, Hill KJ, Iannicelli M, Brancati F, Gabriel SB, Russ C, Logan CV, Sharif SM, Bennett CP, Abe M, Hildebrandt F, Diplas BH, Attié-Bitach T, Katsanis N, Rajab A, Koul R, Sztriha L, Waters ER, Ferro-Novick S, Woods CG, Johnson CA, Valente EM, Zaki MS, and Gleeson JG
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Cerebellar Diseases metabolism, Cerebellar Diseases pathology, Cilia metabolism, Conserved Sequence, DNA, Intergenic, Eye Abnormalities metabolism, Eye Abnormalities pathology, Gene Expression Profiling, Genetic Heterogeneity, Humans, Kidney Diseases, Cystic metabolism, Kidney Diseases, Cystic pathology, Membrane Proteins chemistry, Membrane Proteins metabolism, Molecular Sequence Data, Multigene Family, Mutation, Mutation, Missense, Phenotype, Protein Transport, Retina abnormalities, Retina metabolism, Retina pathology, Transport Vesicles metabolism, Transport Vesicles ultrastructure, Cerebellar Diseases genetics, Cilia ultrastructure, Evolution, Molecular, Eye Abnormalities genetics, Gene Expression Regulation, Genetic Loci, Kidney Diseases, Cystic genetics, Membrane Proteins genetics, Regulatory Sequences, Nucleic Acid
- Abstract
Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.
- Published
- 2012
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33. Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome.
- Author
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Lancaster MA, Gopal DJ, Kim J, Saleem SN, Silhavy JL, Louie CM, Thacker BE, Williams Y, Zaki MS, and Gleeson JG
- Subjects
- Abnormalities, Multiple, Adaptor Proteins, Vesicular Transport, Animals, Antigens, Neoplasm, Cell Cycle Proteins, Cerebellar Diseases etiology, Cerebellar Diseases genetics, Cerebellar Diseases pathology, Cerebellum growth & development, Cerebellum pathology, Cerebellum physiology, Cytoskeletal Proteins, Eye Abnormalities etiology, Eye Abnormalities genetics, Eye Abnormalities pathology, Humans, Kidney Diseases, Cystic etiology, Kidney Diseases, Cystic genetics, Kidney Diseases, Cystic pathology, Lithium pharmacology, Magnetic Resonance Imaging, Mice, Mice, Mutant Strains, Nuclear Proteins genetics, Nuclear Proteins physiology, Phenotype, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins physiology, Retina abnormalities, Retina pathology, Signal Transduction drug effects, Signal Transduction physiology, Wnt Proteins genetics, Cerebellum abnormalities, Disease Models, Animal, Wnt Proteins physiology
- Abstract
The ciliopathy Joubert syndrome is marked by cerebellar vermis hypoplasia, a phenotype for which the pathogenic mechanism is unclear. To investigate Joubert syndrome pathogenesis, we have examined mice with mutated Ahi1, the first identified Joubert syndrome-associated gene. These mice show cerebellar hypoplasia with a vermis-midline fusion defect early in development. This defect is concomitant with expansion of the roof plate and is also evident in a mouse mutant for another Joubert syndrome-associated gene, Cep290. Furthermore, fetal magnetic resonance imaging (MRI) of human subjects with Joubert syndrome reveals a similar midline cleft, suggesting parallel pathogenic mechanisms. Previous evidence has suggested a role for Jouberin (Jbn), the protein encoded by Ahi1, in canonical Wnt signaling. Consistent with this, we found decreased Wnt reporter activity at the site of hemisphere fusion in the developing cerebellum of Ahi1-mutant mice. This decrease was accompanied by reduced proliferation at the site of fusion. Finally, treatment with lithium, a Wnt pathway agonist, partially rescued this phenotype. Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert syndrome that can be overcome with Wnt stimulation.
- Published
- 2011
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34. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder.
- Author
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Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Blümel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, and Gleeson JG
- Subjects
- 3-Oxo-5-alpha-Steroid 4-Dehydrogenase genetics, Animals, Butadienes metabolism, Consanguinity, Embryo, Mammalian metabolism, Genome-Wide Association Study, Glycosylation, Hemiterpenes metabolism, Humans, Membrane Proteins genetics, Mice, Pentanes metabolism, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins genetics, Unfolded Protein Response, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase metabolism, Abnormalities, Multiple metabolism, Dolichols metabolism, Intellectual Disability metabolism, Membrane Proteins metabolism, Mutation, Saccharomyces cerevisiae Proteins metabolism
- Abstract
N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5alpha-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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- View/download PDF
35. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes.
- Author
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Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, Iannicelli M, Travaglini L, Romani S, Illi B, Adams M, Szymanska K, Mazzotta A, Lee JE, Tolentino JC, Swistun D, Salpietro CD, Fede C, Gabriel S, Russ C, Cibulskis K, Sougnez C, Hildebrandt F, Otto EA, Held S, Diplas BH, Davis EE, Mikula M, Strom CM, Ben-Zeev B, Lev D, Sagie TL, Michelson M, Yaron Y, Krause A, Boltshauser E, Elkhartoufi N, Roume J, Shalev S, Munnich A, Saunier S, Inglehearn C, Saad A, Alkindy A, Thomas S, Vekemans M, Dallapiccola B, Katsanis N, Johnson CA, Attié-Bitach T, and Gleeson JG
- Subjects
- Abnormalities, Multiple pathology, Amino Acid Sequence, Animals, Base Sequence, Cell Line, Consanguinity, Embryo, Mammalian embryology, Embryo, Mammalian metabolism, Gastrulation genetics, Gene Expression Regulation, Developmental, Genetic Predisposition to Disease, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Humans, In Situ Hybridization, Jews genetics, Microscopy, Confocal, Molecular Sequence Data, Pedigree, Polymorphism, Single Nucleotide, RNA Interference, Syndrome, Zebrafish embryology, Zebrafish genetics, Abnormalities, Multiple genetics, Cilia pathology, Membrane Proteins genetics, Mutation
- Abstract
Joubert syndrome (JBTS), related disorders (JSRDs) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.
- Published
- 2010
- Full Text
- View/download PDF
36. Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies.
- Author
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Bielas SL, Silhavy JL, Brancati F, Kisseleva MV, Al-Gazali L, Sztriha L, Bayoumi RA, Zaki MS, Abdel-Aleem A, Rosti RO, Kayserili H, Swistun D, Scott LC, Bertini E, Boltshauser E, Fazzi E, Travaglini L, Field SJ, Gayral S, Jacoby M, Schurmans S, Dallapiccola B, Majerus PW, Valente EM, and Gleeson JG
- Subjects
- Acetylation, Amino Acid Substitution, Animals, Base Sequence, Brain diagnostic imaging, Case-Control Studies, Catalytic Domain, Cell Line, Chromosomes, Human, Pair 9, Cilia enzymology, Consanguinity, Culture Media, Serum-Free, Fibroblasts metabolism, Fibroblasts ultrastructure, Genetic Linkage, Green Fluorescent Proteins metabolism, Haplotypes, Homozygote, Humans, Hydrolysis, Mice, Mice, Transgenic, Molecular Sequence Data, Mutation, Missense, Phosphatidylinositol 4,5-Diphosphate genetics, Phosphatidylinositol Phosphates genetics, Phosphoric Monoester Hydrolases chemistry, Phosphoric Monoester Hydrolases metabolism, Physical Chromosome Mapping, Pigment Epithelium of Eye cytology, Polymorphism, Single Nucleotide, Protein Structure, Tertiary, Radiography, Serum metabolism, Tubulin metabolism, Cilia pathology, Mutation, Phosphatidylinositols genetics, Phosphoric Monoester Hydrolases genetics, Signal Transduction genetics
- Abstract
Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly and is included in the newly emerging group of 'ciliopathies'. In individuals with Joubert disease genetically linked to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5-phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function.
- Published
- 2009
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37. Impaired Wnt-beta-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy.
- Author
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Lancaster MA, Louie CM, Silhavy JL, Sintasath L, Decambre M, Nigam SK, Willert K, and Gleeson JG
- Subjects
- Adaptor Proteins, Vesicular Transport, Animals, Cilia physiology, Homeostasis, Kidney pathology, Kidney Diseases, Cystic pathology, Mice, Mice, Knockout, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins physiology, Signal Transduction, Kidney physiopathology, Kidney Diseases, Cystic etiology, Kidney Diseases, Cystic physiopathology, Proto-Oncogene Proteins deficiency, Wnt Proteins physiology, beta Catenin physiology
- Abstract
Cystic kidney disease represents a major cause of end-stage renal disease, yet the molecular mechanisms of pathogenesis remain largely unclear. Recent emphasis has been placed on a potential role for canonical Wnt signaling, but investigation of this pathway in adult renal homeostasis is lacking. Here we provide evidence of a previously unidentified canonical Wnt activity in adult mammalian kidney homeostasis, the loss of which leads to cystic kidney disease. Loss of the Jouberin (Jbn) protein in mouse leads to the cystic kidney disease nephronophthisis, owing to an unexpected decrease in endogenous Wnt activity. Jbn interacts with and facilitates beta-catenin nuclear accumulation, resulting in positive modulation of downstream transcription. Finally, we show that Jbn is required in vivo for a Wnt response to injury and renal tubule repair, the absence of which triggers cystogenesis.
- Published
- 2009
- Full Text
- View/download PDF
38. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome.
- Author
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Cantagrel V, Silhavy JL, Bielas SL, Swistun D, Marsh SE, Bertrand JY, Audollent S, Attié-Bitach T, Holden KR, Dobyns WB, Traver D, Al-Gazali L, Ali BR, Lindner TH, Caspary T, Otto EA, Hildebrandt F, Glass IA, Logan CV, Johnson CA, Bennett C, Brancati F, Valente EM, Woods CG, and Gleeson JG
- Subjects
- Abnormalities, Multiple genetics, Animals, Chromosome Mapping, Computational Biology, Conserved Sequence, Humans, Molecular Sequence Data, Neurons metabolism, Syndrome, Zebrafish, ADP-Ribosylation Factors genetics, Brain Diseases genetics, Cilia metabolism, Genetic Predisposition to Disease, Mutation
- Abstract
Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the "molar tooth sign" on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.
- Published
- 2008
- Full Text
- View/download PDF
39. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders.
- Author
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Brancati F, Travaglini L, Zablocka D, Boltshauser E, Accorsi P, Montagna G, Silhavy JL, Barrano G, Bertini E, Emma F, Rigoli L, Dallapiccola B, Gleeson JG, and Valente EM
- Subjects
- Adult, Brain Stem abnormalities, Cerebellum pathology, Child, Preschool, Cohort Studies, DNA Mutational Analysis, Family Health, Female, Genetic Testing, Humans, Kidney pathology, Magnetic Resonance Imaging, Male, Phenotype, Syndrome, Adaptor Proteins, Signal Transducing genetics, Cerebellum abnormalities, Kidney abnormalities, Mutation
- Abstract
Joubert syndrome-related disorders (JSRDs) are autosomal recessive pleiotropic conditions sharing a peculiar cerebellar and brainstem malformation known as the 'molar tooth sign' (MTS). Recently, mutations in a novel ciliary gene, RPGRIP1L, have been shown to cause both JSRDs and Meckel-Gruber syndrome. We searched for RPGRIP1L mutations in 120 patients with proven MTS and phenotypes representative of all JSRD clinical subgroups. Two homozygous mutations, the previously reported p.T615P in exon 15 and the novel c.2268_2269delA in exon 16, were detected in 2 of 16 families with cerebello-renal presentation ( approximately 12%). Conversely, no pathogenic changes were found in patients with other JSRD phenotypes, suggesting that RPGRIP1L mutations are largely confined to the cerebello-renal subgroup, while they overall represent a rare cause of JSRD (<2%).
- Published
- 2008
- Full Text
- View/download PDF
40. The molar tooth sign: a new Joubert syndrome and related cerebellar disorders classification system tested in Egyptian families.
- Author
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Zaki MS, Abdel-Aleem A, Abdel-Salam G, Marsh SE, Silhavy JL, Barkovich AJ, Ross ME, Saleem SN, Dobyns WB, and Gleeson JG
- Subjects
- Abnormalities, Multiple genetics, Atrophy genetics, Atrophy pathology, Atrophy physiopathology, Cerebellar Diseases classification, Chromosome Disorders classification, Chromosome Disorders diagnosis, Chromosome Disorders genetics, Chromosome Mapping, DNA Mutational Analysis, Egypt, Female, Genetic Testing, Genotype, Humans, Kidney Diseases diagnostic imaging, Kidney Diseases genetics, Kidney Diseases physiopathology, Liver Diseases diagnostic imaging, Liver Diseases genetics, Liver Diseases physiopathology, Magnetic Resonance Imaging, Male, Neural Pathways pathology, Neural Pathways physiopathology, Phenotype, Predictive Value of Tests, Retinal Degeneration genetics, Retinal Degeneration pathology, Retinal Degeneration physiopathology, Syndrome, Ultrasonography, Cerebellar Diseases diagnosis, Cerebellar Diseases genetics, Cerebellum pathology, Cerebellum physiopathology, Genetic Predisposition to Disease genetics, Mutation genetics
- Abstract
Joubert syndrome and related cerebellar disorders (JSRD) are a group of recessive congenital ataxia conditions usually showing neonatal hypotonia, dysregulated breathing rhythms, oculomotor apraxia, and mental retardation. The pathognomonic finding in JSRD is the unique molar tooth sign (MTS) on brain imaging. There is a tremendously broad spectrum of signs and symptoms mainly including kidney, retina, and liver disease, along with polydactyly and facial dysmorphisms. Here we propose a new diagnostic classification within JSRD that includes four major subtypes. To test this classification, we performed a systematic recruitment and genetic evaluation from a single referral center in Egypt. Thirteen families were identified, four showed evidence of linkage to one of the four known genetic loci, three showed novel AHI1 mutations, and nine were excluded from known loci. Each family could be classified into one of the four subtypes. This classification may thus be useful in the evaluation of patients with JSRD.
- Published
- 2008
- Full Text
- View/download PDF
41. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders.
- Author
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Brancati F, Barrano G, Silhavy JL, Marsh SE, Travaglini L, Bielas SL, Amorini M, Zablocka D, Kayserili H, Al-Gazali L, Bertini E, Boltshauser E, D'Hooghe M, Fazzi E, Fenerci EY, Hennekam RC, Kiss A, Lees MM, Marco E, Phadke SR, Rigoli L, Romano S, Salpietro CD, Sherr EH, Signorini S, Stromme P, Stuart B, Sztriha L, Viskochil DH, Yuksel A, Dallapiccola B, Valente EM, and Gleeson JG
- Subjects
- Abnormalities, Multiple diagnosis, Adolescent, Adult, Cell Cycle Proteins, Child, Child, Preschool, Cohort Studies, Cytoskeletal Proteins, DNA Mutational Analysis, Female, Humans, Kidney Diseases diagnosis, Magnetic Resonance Imaging, Male, Mutation, Ocular Motility Disorders diagnosis, Phenotype, Syndrome, Abnormalities, Multiple genetics, Antigens, Neoplasm genetics, Brain abnormalities, Kidney Diseases genetics, Molar abnormalities, Neoplasm Proteins genetics, Ocular Motility Disorders genetics
- Abstract
Joubert syndrome-related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Loken syndrome (JSRD-SLS phenotype). Here, we performed comprehensive CEP290-mutation analysis on two nonoverlapping cohorts of JSRD-affected patients with a proven MTS. We identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only two patients. The data suggest that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies.
- Published
- 2007
- Full Text
- View/download PDF
42. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome.
- Author
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Valente EM, Silhavy JL, Brancati F, Barrano G, Krishnaswami SR, Castori M, Lancaster MA, Boltshauser E, Boccone L, Al-Gazali L, Fazzi E, Signorini S, Louie CM, Bellacchio E, Bertini E, Dallapiccola B, and Gleeson JG
- Subjects
- Animals, Antigens, Neoplasm metabolism, Cell Cycle Proteins, Centrosome metabolism, Cytoskeletal Proteins, Humans, Mice, Neoplasm Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Syndrome, Antigens, Neoplasm genetics, Brain abnormalities, Mutation, Neoplasm Proteins genetics
- Abstract
Joubert syndrome-related disorders (JSRD) are a group of syndromes sharing the neuroradiological features of cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the 'molar tooth sign'. We identified mutations in the CEP290 gene in five families with variable neurological, retinal and renal manifestations. CEP290 expression was detected mostly in proliferating cerebellar granule neuron populations and showed centrosome and ciliary localization, linking JSRDs to other human ciliopathies.
- Published
- 2006
- Full Text
- View/download PDF
43. Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria.
- Author
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Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, Al-Gazali L, Al-Tawari AA, Kayserili H, Sztriha L, and Gleeson JG
- Subjects
- Abnormalities, Multiple pathology, Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Amino Acid Sequence, Base Sequence, Blotting, Northern, Cerebellum pathology, Conserved Sequence genetics, DNA Mutational Analysis, Gene Components, Humans, Molecular Sequence Data, Pedigree, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Syndrome, Abnormalities, Multiple genetics, Cerebellum abnormalities, Mutation genetics, Nerve Tissue Proteins genetics, Phenotype
- Abstract
Joubert syndrome (JS) is an autosomal recessive disorder marked by agenesis of the cerebellar vermis, ataxia, hypotonia, oculomotor apraxia, neonatal breathing abnormalities, and mental retardation. Despite the fact that this condition was described >30 years ago, the molecular basis has remained poorly understood. Here, we identify two frameshift mutations and one missense mutation in the AHI1 gene in three consanguineous families with JS, some with cortical polymicrogyria. AHI1, encoding the Jouberin protein, is an alternatively spliced signaling molecule that contains seven Trp-Asp (WD) repeats, an SH3 domain, and numerous SH3-binding sites. The gene is expressed strongly in embryonic hindbrain and forebrain, and our data suggest that AHI1 is required for both cerebellar and cortical development in humans. The recently described mutations in NPHP1, encoding a protein containing an SH3 domain, in a subset of patients with JS plus nephronophthisis, suggest a shared pathway.
- Published
- 2004
- Full Text
- View/download PDF
44. Complete genomic sequence of bacteriophage B3, a Mu-like phage of Pseudomonas aeruginosa.
- Author
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Braid MD, Silhavy JL, Kitts CL, Cano RJ, and Howe MM
- Subjects
- Base Sequence, Biological Evolution, Molecular Sequence Data, Multigene Family, Open Reading Frames, Transposases physiology, DNA, Viral chemistry, Genome, Viral, Pseudomonas Phages genetics, Pseudomonas aeruginosa virology
- Abstract
Bacteriophage B3 is a transposable phage of Pseudomonas aeruginosa. In this report, we present the complete DNA sequence and annotation of the B3 genome. DNA sequence analysis revealed that the B3 genome is 38,439 bp long with a G+C content of 63.3%. The genome contains 59 proposed open reading frames (ORFs) organized into at least three operons. Of these ORFs, the predicted proteins from 41 ORFs (68%) display significant similarity to other phage or bacterial proteins. Many of the predicted B3 proteins are homologous to those encoded by the early genes and head genes of Mu and Mu-like prophages found in sequenced bacterial genomes. Only two of the predicted B3 tail proteins are homologous to other well-characterized phage tail proteins; however, several Mu-like prophages and transposable phage D3112 encode approximately 10 highly similar proteins in their predicted tail gene regions. Comparison of the B3 genomic organization with that of Mu revealed evidence of multiple genetic rearrangements, the most notable being the inversion of the proposed B3 immunity/early gene region, the loss of Mu-like tail genes, and an extreme leftward shift of the B3 DNA modification gene cluster. These differences illustrate and support the widely held view that tailed phages are genetic mosaics arising by the exchange of functional modules within a diverse genetic pool.
- Published
- 2004
- Full Text
- View/download PDF
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