The Experts below are selected from a list of 1311 Experts worldwide ranked by ideXlab platform
Maurizio Genuardi - One of the best experts on this subject based on the ideXlab platform.
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Clinical and genetic study of a family with a paternally inherited 15q11-q13 duplication.
American journal of medical genetics. Part A, 2013Co-Authors: Carla Marini, Antonella Cecconi, Elisa Contini, Marilena Pantaleo, Tiziana Metitieri, Silvia Guarducci, Sabrina Giglio, Renzo Guerrini, Maurizio GenuardiAbstract:Interstitial chromosome 15q11-q13 duplications are associated with developmental delay, behavioral problems and additional manifestations, including epilepsy. In most affected individuals the duplicated chromosome is maternally derived, whereas paternal inheritance is more often associated with a normal phenotype. Seizures have not been described in patients with paternal dup 15q11-q13. We describe a family with five individuals in three generations with a paternally-inherited 15q11-q13 duplication, four of whom exhibited abnormal phenotypic characteristics, including seizures. The 18-year-old female proband presented with moderate intellectual disability, obesity, and epilepsy. Her brother manifested learning disability and behavioral problems. They both inherited the 15q11-q13 dup from their father who had a normal phenotype. Their paternal uncle and grandfather also had the duplication and were reported to have had seizures. Array-CGH and MLPA analyses showed that the duplication included the TUBGCP5, CYFIP1, MKRN3, MAGEL2, NDN, SNRPN, UBE3A, ATP10A, GABRB3, GABRA5, GABRG3, and OCA2 genes. This report provides evidence for intrafamilial phenotypic variability of paternal dup 15q11-q13, ranging from normal to intellectual disability and seizures, and potentially expanding the phenotype of paternal 15q11-q13 interstitial duplications.
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Clinical and genetic study of a family with a paternally inherited 15q11-q13 duplication.
American Journal of Medical Genetics Part A, 2013Co-Authors: Carla Marini, Antonella Cecconi, Elisa Contini, Marilena Pantaleo, Tiziana Metitieri, Silvia Guarducci, Sabrina Giglio, Renzo Guerrini, Maurizio GenuardiAbstract:Interstitial chromosome 15q11–q13 duplications are associated with developmental delay, behavioral problems and additional manifestations, including epilepsy. In most affected individuals the duplicated chromosome is maternally derived, whereas paternal inheritance is more often associated with a normal phenotype. Seizures have not been described in patients with paternal dup 15q11–q13. We describe a family with five individuals in three generations with a paternally-inherited 15q11–q13 duplication, four of whom exhibited abnormal phenotypic characteristics, including seizures. The 18-year-old female proband presented with moderate intellectual disability, obesity, and epilepsy. Her brother manifested learning disability and behavioral problems. They both inherited the 15q11–q13 dup from their father who had a normal phenotype. Their paternal uncle and grandfather also had the duplication and were reported to have had seizures. Array-CGH and MLPA analyses showed that the duplication included the TUBGCP5, CYFIP1, MKRN3, MAGEL2, NDN, SNRPN, UBE3A, ATP10A, GABRB3, GABRA5, GABRG3, and OCA2 genes. This report provides evidence for intrafamilial phenotypic variability of paternal dup 15q11–q13, ranging from normal to intellectual disability and seizures, and potentially expanding the phenotype of paternal 15q11–q13 interstitial duplications. © 2013 Wiley Periodicals, Inc.
Jing-qiong Kang - One of the best experts on this subject based on the ideXlab platform.
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Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation.
Cell reports, 2016Co-Authors: Ryan J. Delahanty, Yanfeng Zhang, Terry Jo Bichell, Wangzhen Shen, Kelienne M. Verdier, Robert L. Macdonald, Kelli L. Boyd, Janice Williams, Jing-qiong KangAbstract:Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3, and OCA2. Mutations in GABRB3 have frequently been associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of GABRB3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy. Using exome and RNA sequencing, we confirmed that only the GABRB3 gene was disrupted while the Oca2 gene was intact. However, mRNA abundance of Oca2 and other genes adjacent to GABRB3 is substantially reduced in GABRB3-/- mice, suggesting complex transcriptional regulation in this region. These results suggest that impairment in GABRB3 downregulates OCA2 and indirectly causes ocular hypopigmentation and visual defects in AS and PWS.
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Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism
2016Co-Authors: Ryan J. Delahanty, Jing-qiong Kang, Camille W Brune, Eric Courchesne, Ph. D, O. Kistner, Nancy J CoxAbstract:Maternal 15q11-q13 duplication is the most common copy number variant in autism, accounting for ∼1-3 % of cases. The 15q11-q13 region is subject to epigenetic regulation and genomic copy number losses and gains cause genomic disorders in a parent-of-origin-specific manner. One 15q11-q13 locus encodes the GABAA receptor β3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established. We report that maternal transmission of a GABRB3 signal peptide variant (P11S), previously implicated in childhood absence epilepsy, is associated with autism. Analysis of wild-type and mutant β3 subunit-containing α1β3γ2 GABAA receptors demonstrates reduced whole cell current and decreased β3 subunit protein on the cell surface due to impaired intracellular β3 subunit processing. We thus provide the first evidence for association between a specific GABAA receptor defect and autism, direct evidence that this defect causes synaptic dysfunction that is autism-relevant, and the first maternal risk effect in the 15q11-q13 autism duplication region linked to a coding variant
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maternal transmission of a rare GABRB3 signal peptide variant is associated with autism
Molecular Psychiatry, 2011Co-Authors: Ryan J. Delahanty, Robert L. Macdonald, Jing-qiong Kang, Camille W Brune, Emily O Kistner, Eric Courchesne, Nancy J Cox, Edwin H Cook, James S. SutcliffeAbstract:Maternal 15q11-q13 duplication is the most common copy number variant in autism, accounting for ∼1-3% of cases. The 15q11-q13 region is subject to epigenetic regulation, and genomic copy number losses and gains cause genomic disorders in a parent-of-origin-specific manner. One 15q11-q13 locus encodes the GABA(A) receptor β3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established. We report that maternal transmission of a GABRB3 signal peptide variant (P11S), previously implicated in childhood absence epilepsy, is associated with autism. An analysis of wild-type and mutant β3 subunit-containing α1β3γ2 or α3β3γ2 GABA(A) receptors shows reduced whole-cell current and decreased β3 subunit protein on the cell surface due to impaired intracellular β3 subunit processing. We thus provide the first evidence of an association between a specific GABA(A) receptor defect and autism, direct evidence that this defect causes synaptic dysfunction that is autism relevant and the first maternal risk effect in the 15q11-q13 autism duplication region that is linked to a coding variant.
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mutations in gabaa receptor subunits associated with genetic epilepsies
The Journal of Physiology, 2010Co-Authors: Robert L. Macdonald, Jing-qiong Kang, Martin J GallagherAbstract:Mutations in inhibitory GABAA receptor subunit genes (GABRA1, GABRB3, GABRG2 and GABRD) have been associated with genetic epilepsy syndromes including childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), pure febrile seizures (FS), generalized epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS)/severe myoclonic epilepsy in infancy (SMEI). These mutations are found in both translated and untranslated gene regions and have been shown to affect the GABAA receptors by altering receptor function and/or by impairing receptor biogenesis by multiple mechanisms including reducing subunit mRNA transcription or stability, impairing subunit folding, stability, or oligomerization and by inhibiting receptor trafficking.
Robert L. Macdonald - One of the best experts on this subject based on the ideXlab platform.
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synaptic clustering differences due to different GABRB3 mutations cause variable epilepsy syndromes
Brain, 2019Co-Authors: Yiwu Shi, Wangzhen Shen, Qi Zhang, Kefu Cai, Sarah Poliquin, Nathan Winters, Jie Wang, Robert L. MacdonaldAbstract:GABRB3 is highly expressed early in the developing brain, and its encoded β3 subunit is critical for GABAA receptor assembly and trafficking as well as stem cell differentiation in embryonic brain. To date, over 400 mutations or variants have been identified in GABRB3. Mutations in GABRB3 have been increasingly recognized as a major cause for severe paediatric epilepsy syndromes such as Lennox-Gastaut syndrome, Dravet syndrome and infantile spasms with intellectual disability as well as relatively mild epilepsy syndromes such as childhood absence epilepsy. There is no plausible molecular pathology for disease phenotypic heterogeneity. Here we used a very high-throughput flow cytometry assay to evaluate the impact of multiple human mutations in GABRB3 on receptor trafficking. In this study we found that surface expression of mutant β3 subunits is variable. However, it was consistent that surface expression of partnering γ2 subunits was lower when co-expressed with mutant than with wild-type subunits. Because γ2 subunits are critical for synaptic GABAA receptor clustering, this provides an important clue for understanding the pathophysiology of GABRB3 mutations. To validate our findings further, we obtained an in-depth comparison of two novel mutations [GABRB3 (N328D) and GABRB3 (E357K)] associated with epilepsy with different severities of epilepsy phenotype. GABRB3 (N328D) is associated with the relatively severe Lennox-Gastaut syndrome, and GABRB3 (E357K) is associated with the relatively mild juvenile absence epilepsy syndrome. With functional characterizations in both heterologous cells and rodent cortical neurons by patch-clamp recordings, confocal microscopy and immunoblotting, we found that both the GABRB3 (N328D) and GABRB3 (E357K) mutations reduced total subunit expression in neurons but not in HEK293T cells. Both mutant subunits, however, were reduced on the cell surface and in synapses, but the Lennox-Gastaut syndrome mutant β3 (N328D) subunit was more reduced than the juvenile absence epilepsy mutant β3 (E357K) subunit. Interestingly, both mutant β3 subunits impaired postsynaptic clustering of wild-type GABAA receptor γ2 subunits and prevented γ2 subunits from incorporating into GABAA receptors at synapses, although by different cellular mechanisms. Importantly, wild-type γ2 subunits were reduced and less clustered at inhibitory synapses in GABRB3+/- knockout mice. This suggests that impaired receptor localization to synapses is a common pathophysiological mechanism for GABRB3 mutations, although the extent of impairment may be different among mutant subunits. The study thus identifies the novel mechanism of impaired targeting of receptors containing mutant β3 subunits and provides critical insights into understanding how GABRB3 mutations produce severe epilepsy syndromes and epilepsy phenotypic heterogeneity.
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Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation.
Cell reports, 2016Co-Authors: Ryan J. Delahanty, Yanfeng Zhang, Terry Jo Bichell, Wangzhen Shen, Kelienne M. Verdier, Robert L. Macdonald, Kelli L. Boyd, Janice Williams, Jing-qiong KangAbstract:Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3, and OCA2. Mutations in GABRB3 have frequently been associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of GABRB3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy. Using exome and RNA sequencing, we confirmed that only the GABRB3 gene was disrupted while the Oca2 gene was intact. However, mRNA abundance of Oca2 and other genes adjacent to GABRB3 is substantially reduced in GABRB3-/- mice, suggesting complex transcriptional regulation in this region. These results suggest that impairment in GABRB3 downregulates OCA2 and indirectly causes ocular hypopigmentation and visual defects in AS and PWS.
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maternal transmission of a rare GABRB3 signal peptide variant is associated with autism
Molecular Psychiatry, 2011Co-Authors: Ryan J. Delahanty, Robert L. Macdonald, Jing-qiong Kang, Camille W Brune, Emily O Kistner, Eric Courchesne, Nancy J Cox, Edwin H Cook, James S. SutcliffeAbstract:Maternal 15q11-q13 duplication is the most common copy number variant in autism, accounting for ∼1-3% of cases. The 15q11-q13 region is subject to epigenetic regulation, and genomic copy number losses and gains cause genomic disorders in a parent-of-origin-specific manner. One 15q11-q13 locus encodes the GABA(A) receptor β3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established. We report that maternal transmission of a GABRB3 signal peptide variant (P11S), previously implicated in childhood absence epilepsy, is associated with autism. An analysis of wild-type and mutant β3 subunit-containing α1β3γ2 or α3β3γ2 GABA(A) receptors shows reduced whole-cell current and decreased β3 subunit protein on the cell surface due to impaired intracellular β3 subunit processing. We thus provide the first evidence of an association between a specific GABA(A) receptor defect and autism, direct evidence that this defect causes synaptic dysfunction that is autism relevant and the first maternal risk effect in the 15q11-q13 autism duplication region that is linked to a coding variant.
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mutations in gabaa receptor subunits associated with genetic epilepsies
The Journal of Physiology, 2010Co-Authors: Robert L. Macdonald, Jing-qiong Kang, Martin J GallagherAbstract:Mutations in inhibitory GABAA receptor subunit genes (GABRA1, GABRB3, GABRG2 and GABRD) have been associated with genetic epilepsy syndromes including childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), pure febrile seizures (FS), generalized epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS)/severe myoclonic epilepsy in infancy (SMEI). These mutations are found in both translated and untranslated gene regions and have been shown to affect the GABAA receptors by altering receptor function and/or by impairing receptor biogenesis by multiple mechanisms including reducing subunit mRNA transcription or stability, impairing subunit folding, stability, or oligomerization and by inhibiting receptor trafficking.
Ryan J. Delahanty - One of the best experts on this subject based on the ideXlab platform.
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Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation.
Cell reports, 2016Co-Authors: Ryan J. Delahanty, Yanfeng Zhang, Terry Jo Bichell, Wangzhen Shen, Kelienne M. Verdier, Robert L. Macdonald, Kelli L. Boyd, Janice Williams, Jing-qiong KangAbstract:Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3, and OCA2. Mutations in GABRB3 have frequently been associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of GABRB3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy. Using exome and RNA sequencing, we confirmed that only the GABRB3 gene was disrupted while the Oca2 gene was intact. However, mRNA abundance of Oca2 and other genes adjacent to GABRB3 is substantially reduced in GABRB3-/- mice, suggesting complex transcriptional regulation in this region. These results suggest that impairment in GABRB3 downregulates OCA2 and indirectly causes ocular hypopigmentation and visual defects in AS and PWS.
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Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism
2016Co-Authors: Ryan J. Delahanty, Jing-qiong Kang, Camille W Brune, Eric Courchesne, Ph. D, O. Kistner, Nancy J CoxAbstract:Maternal 15q11-q13 duplication is the most common copy number variant in autism, accounting for ∼1-3 % of cases. The 15q11-q13 region is subject to epigenetic regulation and genomic copy number losses and gains cause genomic disorders in a parent-of-origin-specific manner. One 15q11-q13 locus encodes the GABAA receptor β3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established. We report that maternal transmission of a GABRB3 signal peptide variant (P11S), previously implicated in childhood absence epilepsy, is associated with autism. Analysis of wild-type and mutant β3 subunit-containing α1β3γ2 GABAA receptors demonstrates reduced whole cell current and decreased β3 subunit protein on the cell surface due to impaired intracellular β3 subunit processing. We thus provide the first evidence for association between a specific GABAA receptor defect and autism, direct evidence that this defect causes synaptic dysfunction that is autism-relevant, and the first maternal risk effect in the 15q11-q13 autism duplication region linked to a coding variant
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maternal transmission of a rare GABRB3 signal peptide variant is associated with autism
Molecular Psychiatry, 2011Co-Authors: Ryan J. Delahanty, Robert L. Macdonald, Jing-qiong Kang, Camille W Brune, Emily O Kistner, Eric Courchesne, Nancy J Cox, Edwin H Cook, James S. SutcliffeAbstract:Maternal 15q11-q13 duplication is the most common copy number variant in autism, accounting for ∼1-3% of cases. The 15q11-q13 region is subject to epigenetic regulation, and genomic copy number losses and gains cause genomic disorders in a parent-of-origin-specific manner. One 15q11-q13 locus encodes the GABA(A) receptor β3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established. We report that maternal transmission of a GABRB3 signal peptide variant (P11S), previously implicated in childhood absence epilepsy, is associated with autism. An analysis of wild-type and mutant β3 subunit-containing α1β3γ2 or α3β3γ2 GABA(A) receptors shows reduced whole-cell current and decreased β3 subunit protein on the cell surface due to impaired intracellular β3 subunit processing. We thus provide the first evidence of an association between a specific GABA(A) receptor defect and autism, direct evidence that this defect causes synaptic dysfunction that is autism relevant and the first maternal risk effect in the 15q11-q13 autism duplication region that is linked to a coding variant.
Arthur L Beaudet - One of the best experts on this subject based on the ideXlab platform.
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Altered Ultrasonic Vocalization and Impaired Learning and Memory in Angelman Syndrome Mouse Model with a Large Maternal Deletion from Ube3a to GABRB3
2016Co-Authors: Yonghui Jiang, Murray H. Brilliant, Yanzhen Pan, Li Zhu, Jong Yoo, Isabel Lorenzo, Jeffrey L Noebels, Luis L, Corinne Spencer, Arthur L BeaudetAbstract:Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11–q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11–q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to GABRB3, which inactivated the Ube3a and GABRB3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in GABRB3 gene. Mice with a maternal deletion (m2/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and GABRB3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m2/p+), but not paternal (m+/p2), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment i
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altered ultrasonic vocalization and impaired learning and memory in angelman syndrome mouse model with a large maternal deletion from ube3a to GABRB3
PLOS ONE, 2010Co-Authors: Yonghui Jiang, Murray H. Brilliant, Yanzhen Pan, Li Zhu, Luis Landa, Jong Yoo, Corinne M Spencer, Isabel Lorenzo, Jeffrey L Noebels, Arthur L BeaudetAbstract:Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11–q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11–q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to GABRB3, which inactivated the Ube3a and GABRB3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in GABRB3 gene. Mice with a maternal deletion (m−/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and GABRB3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m−/p+), but not paternal (m+/p−), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to GABRB3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.
