The Experts below are selected from a list of 602265 Experts worldwide ranked by ideXlab platform
Keren J Carss - One of the best experts on this subject based on the ideXlab platform.
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bi allelic Loss of Function cacna1b mutations in progressive epilepsy dyskinesia
American Journal of Human Genetics, 2019Co-Authors: K M Gorman, E Meyer, Detelina Grozeva, Egidio Spinelli, Amy Mctague, Alba Sanchisjuan, Keren J CarssAbstract:The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic Loss-of-Function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic Loss-of-Function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal Function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
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Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia
'Elsevier BV', 2019Co-Authors: K M Gorman, Keren J Carss, Meyer E, Grozeva D, Spinelli E, Mctague A, Sanchis-juan A, Bryant E, Reich A, Al SchneiderAbstract:© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic Loss-of-Function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic Loss-of-Function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal Function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment
Trese Leinderszufall - One of the best experts on this subject based on the ideXlab platform.
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Loss of Function mutations in sodium channel nav1 7 cause anosmia
Nature, 2011Co-Authors: Jan Weiss, Eric Jacobi, Vivienne Willnecker, Samuel J Gossage, Martina Pyrski, Philippe Zizzari, Charles A Greer, Bernd Bufe, Bernhard Schick, Trese LeinderszufallAbstract:Loss of Function of the gene SCN9A, encoding the voltage-gated sodium channel Nav1.7, causes a congenital inability to experience pain in humans. Here we show that Nav1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with Loss-of-Function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Nav1.7 in odour perception, we generated conditional null mice in which Nav1.7 was removed from all olfactory sensory neurons. In the absence of Nav1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell. Humans and mice with mutations in the gene coding for the voltage-gated sodium ion channel Nav1.7, previously shown to be insensitive to pain, are now found to be unable to perceive odours. Olfactory sensory neurons that are missing this sodium channel still produce action potentials, but their synapses fail to transmit to downstream neuronal circuits. The Nav1.7-deficient phenotype of mice resembles that of human patients with Nav1.7 Loss-of-Function mutations, indicating that elimination of this ion channel creates a mouse model of congenital general anosmia.
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Loss of Function mutations in sodium channel nav1 7 cause anosmia
Nature, 2011Co-Authors: Jan Weiss, Eric Jacobi, Vivienne Willnecker, Samuel J Gossage, Martina Pyrski, Philippe Zizzari, Charles A Greer, Bernd Bufe, Bernhard Schick, Trese LeinderszufallAbstract:Loss of Function of the gene SCN9A, encoding the voltage-gated sodium channel Na(v)1.7, causes a congenital inability to experience pain in humans. Here we show that Na(v)1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with Loss-of-Function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Na(v)1.7 in odour perception, we generated conditional null mice in which Na(v)1.7 was removed from all olfactory sensory neurons. In the absence of Na(v)1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell.
Jennifer M Pocock - One of the best experts on this subject based on the ideXlab platform.
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a locked immunometabolic switch underlies trem2 r47h Loss of Function in human ipsc derived microglia
The FASEB Journal, 2020Co-Authors: Thomas M Piers, Katharina Cosker, Anna Mallach, Gabriel Thomas Johnson, Rita Guerreiro, John Hardy, Jennifer M PocockAbstract:Loss-of-Function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic Function in human patient iPSC-derived microglia expressing Loss of Function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular Function such as β-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.
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a locked immunometabolic switch underlies trem2 r47h Loss of Function in human ipsc derived microglia
bioRxiv, 2019Co-Authors: Thomas M Piers, Katharina Cosker, Anna Mallach, Gabriel Thomas Johnson, Rita Guerreiro, John Hardy, Jennifer M PocockAbstract:Abstract Loss-of-Function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2 and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on microglial metabolic Function in human patient iPSC-derived-microglia expressing Loss of Function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer’s disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signalling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular Function such as β-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.
Jan Weiss - One of the best experts on this subject based on the ideXlab platform.
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Loss of Function mutations in sodium channel nav1 7 cause anosmia
Nature, 2011Co-Authors: Jan Weiss, Eric Jacobi, Vivienne Willnecker, Samuel J Gossage, Martina Pyrski, Philippe Zizzari, Charles A Greer, Bernd Bufe, Bernhard Schick, Trese LeinderszufallAbstract:Loss of Function of the gene SCN9A, encoding the voltage-gated sodium channel Nav1.7, causes a congenital inability to experience pain in humans. Here we show that Nav1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with Loss-of-Function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Nav1.7 in odour perception, we generated conditional null mice in which Nav1.7 was removed from all olfactory sensory neurons. In the absence of Nav1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell. Humans and mice with mutations in the gene coding for the voltage-gated sodium ion channel Nav1.7, previously shown to be insensitive to pain, are now found to be unable to perceive odours. Olfactory sensory neurons that are missing this sodium channel still produce action potentials, but their synapses fail to transmit to downstream neuronal circuits. The Nav1.7-deficient phenotype of mice resembles that of human patients with Nav1.7 Loss-of-Function mutations, indicating that elimination of this ion channel creates a mouse model of congenital general anosmia.
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Loss of Function mutations in sodium channel nav1 7 cause anosmia
Nature, 2011Co-Authors: Jan Weiss, Eric Jacobi, Vivienne Willnecker, Samuel J Gossage, Martina Pyrski, Philippe Zizzari, Charles A Greer, Bernd Bufe, Bernhard Schick, Trese LeinderszufallAbstract:Loss of Function of the gene SCN9A, encoding the voltage-gated sodium channel Na(v)1.7, causes a congenital inability to experience pain in humans. Here we show that Na(v)1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with Loss-of-Function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Na(v)1.7 in odour perception, we generated conditional null mice in which Na(v)1.7 was removed from all olfactory sensory neurons. In the absence of Na(v)1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell.
Alba Sanchisjuan - One of the best experts on this subject based on the ideXlab platform.
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bi allelic Loss of Function cacna1b mutations in progressive epilepsy dyskinesia
American Journal of Human Genetics, 2019Co-Authors: K M Gorman, E Meyer, Detelina Grozeva, Egidio Spinelli, Amy Mctague, Alba Sanchisjuan, Keren J CarssAbstract:The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic Loss-of-Function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic Loss-of-Function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal Function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
