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Marc Lalande - One of the best experts on this subject based on the ideXlab platform.
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Parental imprinting and Angelman syndrome.
Advances in neurology, 1999Co-Authors: Marc Lalande, Berge A. Minassian, Timothy M. Delorey, Richard W. OlsenAbstract:Angelman syndrome is an inherited disorder that includes severe mental retardation and epilepsy. Patients have no speech, puppet-like gait with jerky movements, hyperactivity, disturbed sleep, bouts of inappropriate laughter, a pronounced jaw, and widely spaced teeth. The syndrome results from deletion or mutation within maternal chromosome 15q11-q13. Considerable evidence suggests that the gene or genes responsible for Angelman syndrome are expressed only from the maternal chromosome 15, a situation known as parental imprinting. This epigenetic marking of certain regions of the parental genomes is characterized by parent-of-origin-specific allelic DNA methylation, allele-specific DNA replication timing, and physical pairing of the two chromosome 15 homologues. Imprinting is important for normal development, and its disregulation causes several human disorders. The epilepsy of Angelman syndrome has been studied and indicates a rather typical electroencephalographic abnormality with slowing and notched wave and spikes. Various types of seizures occur, usually including myoclonus and atypical absence. Variable severity among patients suggests potential molecular diversity in the genetic mechanism, possibly the involvement of more than one gene. Angelman syndrome can arise from the following molecular genetic defects: a deletion in 15q11-q13 that covers the Angelman gene or genes, mutations that alter imprinting, and paternal uni-parental disomy for the region. Another 20% or so of patients with clinical symptoms of Angelman syndrome have none of these three defects but are believed to have mutations in one or more genes in the region, and this may be familial. The UBE3A gene, which codes for the enzyme ubiquitin protein ligase involved in protein degradation and processing, has been found to be mutated in many but not all of patients with Angelman syndrome and can be considered a major Angelman candidate gene. Other potential candidate genes in the region include a cluster of three GABAA receptor subunits, which are involved in inhibitory synaptic transmission in the brain. The GABRB3 gene, which codes for the beta 3 subunit, is deleted in most persons with Angelman syndrome. The absence of this gene in mice causes craniofacial abnormalities and neurologic impairment with seizures. The exact role of UBE3A and GABRB3 in the syndrome and their imprinting status are under investigation.
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Structure and organization of GABRB3 and GABRA5.
Genomics, 1997Co-Authors: K. Glatt, H. Glatt, Marc LalandeAbstract:The genes encoding the gamma-aminobutyric acid (GABA) type-A receptor subunits beta 3 (GABRB3), alpha 5 (GABRA5), and gamma 3 (GABRG3) map to chromosome 15q11-q13. The three genes are contained within roughly 800 kb of the distal part of the imprinted Prader-Willi and Angelman syndrome region. A 570-kb contig encompassing GABRB3 and GABRA5 has been constructed in P1, lambda phage, and PAC clones. GABRB3 spans 250 kb of DNA and is organized into 9 exons that range from 68 to 504 bp, while GABRA5 is encoded by 11 exons (65 to 924 bp in length) within 86 kb. The exon/intron borders for both genes have been characterized and, primers have been designed to amplify each of the individual exons. Two reference STR markers have been positioned in the contig. The reference STR for GABRB3 is in fact located at least 60 kb beyond the 3' terminus of GABRB3, while D15S97 is contained within intron 4 of GABRB3. The detailed physical map of this GABAA receptor subunit gene cluster should not only be useful in genetic studies of the 15q11-q13 region, but will also be important for investigating the evolution and expression of the GABAA receptor gene superfamily.
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allele specificity of dna replication timing in the angelman prader willi syndrome imprinted chromosomal region
Nature Genetics, 1994Co-Authors: Marc Lalande, Joan H M Knoll, Soude ChengAbstract:DNA replication within chromosome 15q11–q13, a region subject to genomic imprinting, was examined by fluorescence in situ hybridization. Asynchronous replication between homologues was observed in cells from normal individuals and in Prader–Willi (PWS) and Angelman syndrome (AS) patients with chromosome 15 deletions but not in PWS patients with maternal uniparental disomy. Opposite patterns of allele–specific replication timing between homologous loci were observed; paternal early/maternal late at D15S63, D15S10 and the γ–aminobutyric acid receptor β3 subunit gene (GABRB3); and maternal early/paternal late at the more distal γ–aminobutyric acid receptor α5 subunit gene (GABRA5). At the most distal locus examined, D15S12, both patterns of allele–specific replication timing were detected.
Robert L. Macdonald - 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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molecular pathogenic basis for gabrg2 mutations associated with a spectrum of epilepsy syndromes from generalized absence epilepsy to dravet syndrome
JAMA Neurology, 2016Co-Authors: Jing-qiong Kang, Robert L. MacdonaldAbstract:Objective In this review article, we focus on the molecular pathogenic basis for genetic generalized epilepsies associated with mutations in the inhibitory γ-aminobutyric acid (GABA A ) receptor γ2 subunit gene, GABRG2 (OMIM137164), an established epilepsy gene. Observations The γ-aminobutyric acid (GABA A ) receptor γ2 subunit gene, GABRG2 , is abundantly expressed in the mammalian brain, and its encoded γ2 subunit is assembled into αβγ2 receptors, which are the major GABA A receptor isoforms in the brain. The γ2 subunits have a critical role in GABA A receptor trafficking and clustering at synapses. They reside inside the endoplasmic reticulum after synthesis, where they oligomerize with other binding partners, such as α and β subunits, and further assemble into pentameric receptors. Only correctly assembled receptors can traffic beyond the endoplasmic reticulum and reach the cell surface and synapses, where they conduct chloride ion current when activated by GABA. Mutations in GABRG2 have been associated with simple febrile seizures and with genetic epilepsy syndromes, including childhood absence epilepsy, generalized epilepsy with febrile seizures plus, and Dravet syndrome or severe myoclonic epilepsy in infancy. The mutations include missense, nonsense, and frameshift mutations, as well as splice-site and deletion mutations. The mutations have been identified in both coding and noncoding sequences like splice sites. In the coding sequence, these mutations are found in multiple locations, including the extracellular N-terminus, transmembrane domains, and transmembrane 3–transmembrane 4 intracellular loop. All of these mutations reduced channel function but to different extents and by diverse mechanisms, including nonsense-mediated messenger RNA decay, endoplasmic reticulum–associated protein degradation, dominant negative suppression of partnering subunits, mutant subunit aggregation causing cell stress and cell death, and gating defects. Conclusions and Relevance We conclude that the epilepsy phenotypic heterogeneity associated with GABRG2 mutations may be related to the extent of the reduction of GABA A receptor channel function and the differential dominant negative suppression, as well to toxicity related to the metabolism of mutant subunit proteins resulting from each mutant γ2 subunit, in addition to different genetic backgrounds.
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the human epilepsy mutation gabrg2 q390x causes chronic subunit accumulation and neurodegeneration
Nature Neuroscience, 2015Co-Authors: Jing-qiong Kang, Wangzhen Shen, Chengwen Zhou, Robert L. MacdonaldAbstract:Genetic epilepsy and neurodegenerative diseases are two common neurological disorders that are conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies who have impaired development and often go on to die of their disease respond poorly to anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported that multiple GABAA receptor epilepsy mutations result in protein misfolding and abnormal receptor trafficking. We have now developed a model of a severe human genetic epileptic encephalopathy, the Gabrg2(+/Q390X) knock-in mouse. We found that, in addition to impairing inhibitory neurotransmission, mutant GABAA receptor γ2(Q390X) subunits accumulated and aggregated intracellularly, activated caspase 3 and caused widespread, age-dependent neurodegeneration. These findings suggest that the fundamental protein metabolism and cellular consequences of the epilepsy-associated mutant γ2(Q390X) ion channel subunit are not fundamentally different from those associated with neurodegeneration. Our results have far-reaching relevance for the identification of conserved pathological cascades and mechanism-based therapies that are shared between genetic epilepsies and neurodegenerative diseases.
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GAbAA Receptor Subunit Rare Variants Identified in Patients with Idiopathic Generalized Epilepsy Alter Receptor Gating and Assembly
Biophysical Journal, 2013Co-Authors: Ciria C. Hernandez, Katharine N. Gurba, Robert L. MacdonaldAbstract:Exome sequencing of ion channel genes from cases with well characterized idiopathic generalized epilepsies (IGEs) has identified many rare, nonsynonymous single nucleotide polymorphysms (nSNPs) in the human non-epilepsy genes GABRA4, GABRA5, GABRA6, GABRB1, GABRB2, GABRG1 and GABRG3. Structural homology modeling predicts that the rare variants are mainly localized between the agonist-binding domain (N-terminus) and the channel gate (transmembrane domain, TM) of GABAA receptor subunits. We sought to investigate the effects of the rare nSNPs on assembly and function of GABAA receptors containing one of seven separate IGE-associated rare variants identified in α5 and β2 subunits (α5V204I, W280R, S402A, P453L, A459T; β2R293W, R354C), which are located within the well-defined structural GABAA receptor domains. We studied gating properties and surface expression of wild-type (wt) α5β3γ2, α1β2γ2 and mutant (mut) α5(mut)β3γ2, α1β2(mut)γ2 receptors expressed in HEK293T cells. We found that variants located within the N-terminal domain and in the juxtamembrane interface displayed gating or mixed gating and trafficking defects. Furthermore, variants within TMs displayed trafficking defects, but those within the cytoplasmic loop had no defect. Thus, variant subunits α5V204I and β2R293W displayed a mixed profile, causing both gating and trafficking defects of α5β3γ2 and α1β2γ2 receptors, whereas variant α5W280R subunit caused primarily impaired trafficking of α5β3γ2 receptors. Interestingly, homology modeling predicted that α5W280R and β2R293W variants stabilize new hydrogen bonds across the β/α subunit interface, which seems to be essential for inter-subunit interactions in assembled receptors. These findings suggest that gating and/or trafficking defects might suggest that a specific variant may be a susceptibility gene and may help to predict functional risk for loss of GABAergic function in individual IGE cases.NIH funding NS33300 to Robert Macdonald.
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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.
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.
Carla Marini - 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.
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Mutant GABA_A receptor γ2-subunit in childhood absence epilepsy and febrile seizures
Nature Genetics, 2001Co-Authors: Robyn H. Wallace, Carla Marini, Louise A Harkin, John C Mulley, Steven Petrou, David N. Bowser, Rekha G. Panchal, David A. Williams, Grant R. Sutherland, Ingrid E SchefferAbstract:Epilepsies affect at least 2% of the population at some time in life, and many forms have genetic determinants^ 1 , 2 . We have found a mutation in a gene encoding a GABA_A receptor subunit in a large family with epilepsy. The two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS). There is a recognized genetic relationship between FS and CAE, yet the two syndromes have different ages of onset, and the physiology of absences and convulsions is distinct. This suggests the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. We found that the mutation in GABRG2 (encoding the γ2-subunit) abolished in vitro sensitivity to diazepam, raising the possibility that endozepines do in fact exist and have a physiological role in preventing seizures.
Joan H M Knoll - One of the best experts on this subject based on the ideXlab platform.
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allele specificity of dna replication timing in the angelman prader willi syndrome imprinted chromosomal region
Nature Genetics, 1994Co-Authors: Marc Lalande, Joan H M Knoll, Soude ChengAbstract:DNA replication within chromosome 15q11–q13, a region subject to genomic imprinting, was examined by fluorescence in situ hybridization. Asynchronous replication between homologues was observed in cells from normal individuals and in Prader–Willi (PWS) and Angelman syndrome (AS) patients with chromosome 15 deletions but not in PWS patients with maternal uniparental disomy. Opposite patterns of allele–specific replication timing between homologous loci were observed; paternal early/maternal late at D15S63, D15S10 and the γ–aminobutyric acid receptor β3 subunit gene (GABRB3); and maternal early/paternal late at the more distal γ–aminobutyric acid receptor α5 subunit gene (GABRA5). At the most distal locus examined, D15S12, both patterns of allele–specific replication timing were detected.
