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Mark I. Rees - One of the best experts on this subject based on the ideXlab platform.
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ethnicity can predict glra1 genotypes in Hyperekplexia
Journal of Neurology Neurosurgery and Psychiatry, 2015Co-Authors: Rhys H Thomas, Sian-elin Wood, Seo-kyung Chung, C L Hammond, Cheney Drew, Mark I. ReesAbstract:Objectives: Hyperekplexia is predominantly caused by mutations in the α-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance. Methods: We carefully ascertained reports of ethnicity from our Hyperekplexia research cohort. These were compared with all published cases of Hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American. Results: We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p<0.001). In contrast, the dominant point mutation R271 is seen in people of Asian, Caucasian and African-American heritage (n=19) but not in people with Arab or Turkish ethnicities (p<0.001). Conclusions: Self-declared ethnicity can predict gene-screening outcomes. Cultural practices influence the inheritance patterns and a Caucasian founder is postulated for R271 mutations.
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MECHANISMS OF DISEASE IN THE HyperekplexiaS
Journal of Neurology Neurosurgery & Psychiatry, 2014Co-Authors: Mark I. Rees, Sian-elin Wood, Seo-kyung ChungAbstract:Aims To identify mutations associated with Hyperekplexia and to investigate the underlying pathophysiological mechanism of novel mutations identified, whilst providing a genetic diagnosis of Hyperekplexia in the cases referred. Method As part of an ongoing screening program we have analysed the entire coding regions of GLRA1, GLRB and SLC6A5 in 234 Hyperekplexia patients referred to our screening project. All sequence variants were regarded as mutations after exclusion from a panel of human controls. The expression and functional properties of novel GLRA1 variants were analysed using immunocytochemistry and patch-clamp electrophysiology. Results Direct sequencing analysis of GLRA1, GLRB and SLC6A5 revealed mutations in 98 (98/234, 42%) individuals. The majority of mutations were identified in GLRA1 accounting for 60% (59/98) of gene-positive cases. Consistent with previous studies, recessive inheritance was more common. Functional analysis revealed trafficking defects as the major mechanism underlying recessive mutations, whereas dominant mutations primarily affected functional ion channel properties. Conclusion Novel mutations in GLRA1, GLRB and SLC6A5 were identified contributing to the compendium of reported Hyperekplexia mutations. Underlying pathophysiological effects of the novel glycinergic mutations were determined, providing evidence for ion channel disruption, trafficking defects, leaky tonic currents, and loss of function effects.
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Ethnicity can predict GLRA1 genotypes in Hyperekplexia
Journal of neurology neurosurgery and psychiatry, 2014Co-Authors: Rhys H Thomas, Sian-elin Wood, Seo-kyung Chung, C L Hammond, Cheney Drew, Mark I. ReesAbstract:Objectives: Hyperekplexia is predominantly caused by mutations in the α-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance. Methods: We carefully ascertained reports of ethnicity from our Hyperekplexia research cohort. These were compared with all published cases of Hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American. Results: We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p
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Neonatal Hyperekplexia with homozygous p.R392H mutation in GLRA1
Epileptic disorders : international epilepsy journal with videotape, 2014Co-Authors: F. Hmami, Sian-elin Wood, Sana Chaouki, A. Oulmaati, Mustapha Hida, Mark I. Rees, Seo-kyung Chung, Abdelhak BouharrouAbstract:Hyperekplexia is a rare neurogenetic disorder, frequently misdiagnosed in neonates with a risk of apnoea, asphyxia, and sudden infant death. We present video sequences of a male newborn, admitted on the second day of life to the neonatal intensive care unit, due to tonic-clonic movements. Following clinical and paraclinical investigations, a final diagnosis of Hyperekplexia was made. Genetic analysis revealed a homozygous mutation in GLRA1 resulting in a R392H amino acid substitution and altered receptor dynamics, as indicated from previous work. The infant showed a marked improvement of the startle response and muscle hypertonia with clonazepam which is a strong clinical feature of GLRA1-mediated Hyperekplexia. [Published with video sequences]
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PO.04 Ethnic variation in GLRA1 genotype in Hyperekplexia [Conference Abstract]
Journal of Neurology Neurosurgery & Psychiatry, 2011Co-Authors: Rhys H Thomas, Seo-kyung Chung, A Robinson, C L Hammond, Mark I. ReesAbstract:Introduction Mutations in the alpha one subunit of the glycine receptor (GLRA1) cause the majority of genetic (hereditary) Hyperekplexia. Three-quarters of cases show autosomal recessive inheritance and some ethic variation has been described. Methods We undertook a review of all published cases of Hyperekplexia with a genetic cause alongside mutations identified as part of our research. Ethnicities were defined by the referring clinician and then subgrouped into five categories—Caucasian, Asian, Arabic, Turkish and Afro-American. Results 37/53 cases from the literature had a published ethnicity; we included an additional thirty unpublished cases. Homozygous deletions of exons one to six are exclusively seen in people of Turkish descent (n=12, p Conclusion No clear founder effect was seen in R271 cases. Hyperekplexia does show regional and ethnic variation but is it present but recognised in populations where it is less prevalent? Hyperekplexia due to R271 mutations shows dominant inheritance and the deletions of exons one to six are recessive; meaning that the inheritance pattern can be in part predicted by someone9s estimated ethnicity.
Seo-kyung Chung - One of the best experts on this subject based on the ideXlab platform.
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ethnicity can predict glra1 genotypes in Hyperekplexia
Journal of Neurology Neurosurgery and Psychiatry, 2015Co-Authors: Rhys H Thomas, Sian-elin Wood, Seo-kyung Chung, C L Hammond, Cheney Drew, Mark I. ReesAbstract:Objectives: Hyperekplexia is predominantly caused by mutations in the α-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance. Methods: We carefully ascertained reports of ethnicity from our Hyperekplexia research cohort. These were compared with all published cases of Hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American. Results: We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p<0.001). In contrast, the dominant point mutation R271 is seen in people of Asian, Caucasian and African-American heritage (n=19) but not in people with Arab or Turkish ethnicities (p<0.001). Conclusions: Self-declared ethnicity can predict gene-screening outcomes. Cultural practices influence the inheritance patterns and a Caucasian founder is postulated for R271 mutations.
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MECHANISMS OF DISEASE IN THE HyperekplexiaS
Journal of Neurology Neurosurgery & Psychiatry, 2014Co-Authors: Mark I. Rees, Sian-elin Wood, Seo-kyung ChungAbstract:Aims To identify mutations associated with Hyperekplexia and to investigate the underlying pathophysiological mechanism of novel mutations identified, whilst providing a genetic diagnosis of Hyperekplexia in the cases referred. Method As part of an ongoing screening program we have analysed the entire coding regions of GLRA1, GLRB and SLC6A5 in 234 Hyperekplexia patients referred to our screening project. All sequence variants were regarded as mutations after exclusion from a panel of human controls. The expression and functional properties of novel GLRA1 variants were analysed using immunocytochemistry and patch-clamp electrophysiology. Results Direct sequencing analysis of GLRA1, GLRB and SLC6A5 revealed mutations in 98 (98/234, 42%) individuals. The majority of mutations were identified in GLRA1 accounting for 60% (59/98) of gene-positive cases. Consistent with previous studies, recessive inheritance was more common. Functional analysis revealed trafficking defects as the major mechanism underlying recessive mutations, whereas dominant mutations primarily affected functional ion channel properties. Conclusion Novel mutations in GLRA1, GLRB and SLC6A5 were identified contributing to the compendium of reported Hyperekplexia mutations. Underlying pathophysiological effects of the novel glycinergic mutations were determined, providing evidence for ion channel disruption, trafficking defects, leaky tonic currents, and loss of function effects.
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Ethnicity can predict GLRA1 genotypes in Hyperekplexia
Journal of neurology neurosurgery and psychiatry, 2014Co-Authors: Rhys H Thomas, Sian-elin Wood, Seo-kyung Chung, C L Hammond, Cheney Drew, Mark I. ReesAbstract:Objectives: Hyperekplexia is predominantly caused by mutations in the α-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance. Methods: We carefully ascertained reports of ethnicity from our Hyperekplexia research cohort. These were compared with all published cases of Hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American. Results: We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p
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Neonatal Hyperekplexia with homozygous p.R392H mutation in GLRA1
Epileptic disorders : international epilepsy journal with videotape, 2014Co-Authors: F. Hmami, Sian-elin Wood, Sana Chaouki, A. Oulmaati, Mustapha Hida, Mark I. Rees, Seo-kyung Chung, Abdelhak BouharrouAbstract:Hyperekplexia is a rare neurogenetic disorder, frequently misdiagnosed in neonates with a risk of apnoea, asphyxia, and sudden infant death. We present video sequences of a male newborn, admitted on the second day of life to the neonatal intensive care unit, due to tonic-clonic movements. Following clinical and paraclinical investigations, a final diagnosis of Hyperekplexia was made. Genetic analysis revealed a homozygous mutation in GLRA1 resulting in a R392H amino acid substitution and altered receptor dynamics, as indicated from previous work. The infant showed a marked improvement of the startle response and muscle hypertonia with clonazepam which is a strong clinical feature of GLRA1-mediated Hyperekplexia. [Published with video sequences]
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genotype phenotype correlations in Hyperekplexia apnoeas learning difficulties and speech delay
Brain, 2013Co-Authors: Seo-kyung Chung, Rhys H Thomas, C L Hammond, Jean-francois Vanbellinghen, Cheney Drew, Sian Wood, Thomas D Cushion, Jonathan G L MullinsAbstract:Congenital Hyperekplexia is a rare, potentially treatable neuromotor disorder. Three major genes of effect are known, and all three affect glycinergic neurotransmission. Two genes encode for subunits of the postsynaptic inhibitory glycine receptor, GLRA1 encoding the α1 subunit and GLRB encoding the β subunit. The third, SLC6A5, encodes the cognate presynaptic glycine transporter 2. Ninety-seven individuals had a clinical diagnosis of Hyperekplexia confirmed by genetic testing: 61 cases had mutations in GLRA1, 24 cases in SLC6A5 and 12 in GLRB. Detailed retrospective clinical analysis ascertained that all gene-positive cases present in the neonatal period (occasionally prenatally) and that clonazepam is the treatment of choice (95% found it to be efficacious). We confirm that Hyperekplexia is predominantly a recessive condition but dominant cases are seen (16%). We found no genetic evidence for ‘major’ or ‘minor’ forms of Hyperekplexia on a population basis. Thirty-five gene-negative cases were studied for comparison, their cardinal feature was presentation after the first month of life (P < 0.001). In addition to the characteristic ‘stiffness, startles and stumbles’ of Hyperekplexia, apnoea attacks (50 of 89) and delayed development (47 of 92) were frequently reported. Patients with SLC6A5 mutations were significantly more likely to have had recurrent infantile apnoeas (RR1.9; P < 0.005) than those with GLRA1 mutations. Patients with GLRB and SLC6A5 mutations were more likely to have developmental delay (RR1.5 P < 0.01; RR1.9 P < 0.03) than those with GLRA1 mutations; 92% of GLRB cases reported a mild to severe delay in speech acquisition. Molecular modelling of pathogenic mutations demonstrates specific patterns of protein disruption that can be used to predict phenotype severity. The developmental delay in Hyperekplexia, and speech acquisition in particular, may represent failure of developmental neural networks or subtle neurogenic migration defects in the absence of presynaptic glycine release. We recommend early genetic testing for symptomatic neonates and possibly preconception counselling for those at risk for GLRB and SLC6A5 mutations, because of the more challenging phenotype.
Wei Xiong - One of the best experts on this subject based on the ideXlab platform.
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the synthetic cannabinoid dehydroxylcannabidiol restores the function of a major gabaa receptor isoform in a cell model of Hyperekplexia
Journal of Biological Chemistry, 2020Co-Authors: Guichang Zou, Wei Xiong, Jing Xia, Qianqian Han, Dan LiuAbstract:The functions of the glycine receptor (GlyR) and GABAA receptor (GABAAR) are both impaired in Hyperekplexia, a neurological disorder usually caused by GlyR mutations. Although emerging evidence indicates that cannabinoids can directly restore normal GlyR function, whether they affect GABAAR in Hyperekplexia remains unknown. Here we show that dehydroxylcannabidiol (DH-CBD), a synthetic nonpsychoactive cannabinoid, restores the GABA- and glycine-activated currents (IGABA and IGly , respectively) in HEK293 cells coexpressing a major GABAAR isoform (α1β2γ2) and GlyRα1 carrying a human Hyperekplexia-associated mutation (GlyRα1R271Q). Using coimmunoprecipitation and FRET assays, we found that DH-CBD disrupts the protein interaction between GABAAR and GlyRα1R271Q Furthermore, a point mutation of GlyRα1, changing Ser-296 to Ala-296, which is critical for cannabinoid binding on GlyR, significantly blocked DH-CBD-induced restoration of IGABA and IGly currents. This S296A substitution also considerably attenuated DH-CBD-induced disruption of the interaction between GlyRα1R271Q and GABAAR. These findings suggest that, because it restores the functions of both GlyRα1 and GABAAR, DH-CBD may represent a potentially valuable candidate drug to manage Hyperekplexia.
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human hyperekplexic mutations in glycine receptors disinhibit the brainstem by hijacking gabaa receptors
iScience, 2019Co-Authors: Qi Chen, Kai Chen, Yushu Ge, Li Zhang, Wei XiongAbstract:Summary Hyperekplexia disease is usually caused by naturally occurring point mutations in glycine receptors (GlyRs). However, the γ-aminobutyric acid type A receptor (GABAAR) seems to be also involved regarding the therapeutic basis for Hyperekplexia using benzodiazepines, which target GABAARs but not GlyRs. Here, we show that the function of GABAARs was significantly impaired in the hypoglossal nucleus of hyperekplexic transgenic mice. Such impairment appeared to be mediated by interaction between GABAAR and mutant GlyR. The GABAAR dysfunction was caused only by mutant GlyR consisting of homomeric α1 subunits, which locate primarily at pre- and extra-synaptic sites. In addition, the rescue effects of diazepam were attenuated by Xli-093, which specifically blocked diazepam-induced potentiation on α5-containing GABAAR, a major form of pre- and extra-synaptic GABAAR in the brainstem. Thus, our results suggest that the pre- and extra-synaptic GABAARs could be a potential therapeutic target for Hyperekplexia disease caused by GlyR mutations.
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presynaptic glycine receptors as a potential therapeutic target for Hyperekplexia disease
Nature Neuroscience, 2014Co-Authors: Wei Xiong, Shao Rui Chen, Kejun Cheng, Yi Lin Zhao, Hong Chen, Gregg E Homanics, John H Peever, Kenner C Rice, Hui Lin Pan, Li ZhangAbstract:Although postsynaptic glycine receptors (GlyRs) as αβ heteromers attract considerable research attention, little is known about the role of presynaptic GlyRs, likely α homomers, in diseases. Here, we demonstrate that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile startle responses in mice bearing point mutations in α1 GlyRs that are responsible for a hereditary startle-Hyperekplexia disease. The GlyRs expressed as α1 homomers either in HEK-293 cells or at presynaptic terminals of the calyceal synapses in the auditory brainstem are more vulnerable than heteromers to Hyperekplexia mutation-induced impairment. Homomeric mutants are more sensitive to DH-CBD than are heteromers, suggesting presynaptic GlyRs as a primary target. Consistent with this idea, DH-CBD selectively rescues impaired presynaptic GlyR activity and diminished glycine release in the brainstem and spinal cord of hyperekplexic mutant mice. Thus, presynaptic α1 GlyRs emerge as a potential therapeutic target for dominant Hyperekplexia disease and other diseases with GlyR deficiency.
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Presynaptic glycine receptors as a potential therapeutic target for Hyperekplexia disease
Nature Neuroscience, 2014Co-Authors: Wei Xiong, Shao Rui Chen, Kejun Cheng, Yi Lin Zhao, Hong Chen, Gregg E Homanics, John H Peever, Liming He, De-pei Li, Kenner C RiceAbstract:Although postsynaptic glycine receptors (GlyRs) as αβ heteromers attract considerable research attention, little is known about the role of presynaptic GlyRs, likely α homomers, in diseases. Here, we demonstrate that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile startle responses in mice bearing point mutations in α1 GlyRs that are responsible for a hereditary startle-Hyperekplexia disease. The GlyRs expressed as α1 homomers either in HEK-293 cells or at presynaptic terminals of the calyceal synapses in the auditory brainstem are more vulnerable than heteromers to Hyperekplexia mutation–induced impairment. Homomeric mutants are more sensitive to DH-CBD than are heteromers, suggesting presynaptic GlyRs as a primary target. Consistent with this idea, DH-CBD selectively rescues impaired presynaptic GlyR activity and diminished glycine release in the brainstem and spinal cord of hyperekplexic mutant mice. Thus, presynaptic α1 GlyRs emerge as a potential therapeutic target for dominant Hyperekplexia disease and other diseases with GlyR deficiency. The authors show that a nonpsychoactive cannabinoid, DH-CBD, can rescue exaggerated acoustic startle phenotypes caused by startle disease–causing point mutations in the glycine receptor (GlyR) α1 subunit. Homomeric and presynaptic GlyRs showed significant impairment as a result of these mutations, which was selectively rescued by DH-CBD.
Rhys H Thomas - One of the best experts on this subject based on the ideXlab platform.
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ethnicity can predict glra1 genotypes in Hyperekplexia
Journal of Neurology Neurosurgery and Psychiatry, 2015Co-Authors: Rhys H Thomas, Sian-elin Wood, Seo-kyung Chung, C L Hammond, Cheney Drew, Mark I. ReesAbstract:Objectives: Hyperekplexia is predominantly caused by mutations in the α-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance. Methods: We carefully ascertained reports of ethnicity from our Hyperekplexia research cohort. These were compared with all published cases of Hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American. Results: We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p<0.001). In contrast, the dominant point mutation R271 is seen in people of Asian, Caucasian and African-American heritage (n=19) but not in people with Arab or Turkish ethnicities (p<0.001). Conclusions: Self-declared ethnicity can predict gene-screening outcomes. Cultural practices influence the inheritance patterns and a Caucasian founder is postulated for R271 mutations.
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Ethnicity can predict GLRA1 genotypes in Hyperekplexia
Journal of neurology neurosurgery and psychiatry, 2014Co-Authors: Rhys H Thomas, Sian-elin Wood, Seo-kyung Chung, C L Hammond, Cheney Drew, Mark I. ReesAbstract:Objectives: Hyperekplexia is predominantly caused by mutations in the α-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance. Methods: We carefully ascertained reports of ethnicity from our Hyperekplexia research cohort. These were compared with all published cases of Hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American. Results: We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p
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new Hyperekplexia mutations provide insight into glycine receptor assembly trafficking and activation mechanisms
Journal of Biological Chemistry, 2013Co-Authors: Anna Bode, Sian-elin Wood, Rhys H Thomas, Amira Masri, Angelo Keramidas, Cheney Drew, Thomas D Cushion, William O. Pickrell, Jonathon G L Mullins, Elizabeth JonesAbstract:Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage to Hyperekplexia. Most Hyperekplexia cases are caused by mutations in the α1 subunit of the human glycine receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated Hyperekplexia probands for GLRA1 mutations and identified 19 mutations, of which 9 were novel. Electrophysiological analysis demonstrated that the dominant mutations p.Q226E, p.V280M, and p.R414H induced spontaneous channel activity, indicating that this is a recurring mechanism in hGlyR pathophysiology. p.Q226E, at the top of TM1, most likely induced tonic activation via an enhanced electrostatic attraction to p.R271 at the top of TM2, suggesting a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X precluded cell surface expression unless co-expressed with α1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated α1 or α1 plus β subunits. These aberrant receptors exhibit significantly reduced glycine sensitivity. To our knowledge, this is the first suggestion that subunits lacking TM4 domains might be incorporated into functional pentameric ligand-gated ion channel receptors.
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genotype phenotype correlations in Hyperekplexia apnoeas learning difficulties and speech delay
Brain, 2013Co-Authors: Seo-kyung Chung, Rhys H Thomas, C L Hammond, Jean-francois Vanbellinghen, Cheney Drew, Sian Wood, Thomas D Cushion, Jonathan G L MullinsAbstract:Congenital Hyperekplexia is a rare, potentially treatable neuromotor disorder. Three major genes of effect are known, and all three affect glycinergic neurotransmission. Two genes encode for subunits of the postsynaptic inhibitory glycine receptor, GLRA1 encoding the α1 subunit and GLRB encoding the β subunit. The third, SLC6A5, encodes the cognate presynaptic glycine transporter 2. Ninety-seven individuals had a clinical diagnosis of Hyperekplexia confirmed by genetic testing: 61 cases had mutations in GLRA1, 24 cases in SLC6A5 and 12 in GLRB. Detailed retrospective clinical analysis ascertained that all gene-positive cases present in the neonatal period (occasionally prenatally) and that clonazepam is the treatment of choice (95% found it to be efficacious). We confirm that Hyperekplexia is predominantly a recessive condition but dominant cases are seen (16%). We found no genetic evidence for ‘major’ or ‘minor’ forms of Hyperekplexia on a population basis. Thirty-five gene-negative cases were studied for comparison, their cardinal feature was presentation after the first month of life (P < 0.001). In addition to the characteristic ‘stiffness, startles and stumbles’ of Hyperekplexia, apnoea attacks (50 of 89) and delayed development (47 of 92) were frequently reported. Patients with SLC6A5 mutations were significantly more likely to have had recurrent infantile apnoeas (RR1.9; P < 0.005) than those with GLRA1 mutations. Patients with GLRB and SLC6A5 mutations were more likely to have developmental delay (RR1.5 P < 0.01; RR1.9 P < 0.03) than those with GLRA1 mutations; 92% of GLRB cases reported a mild to severe delay in speech acquisition. Molecular modelling of pathogenic mutations demonstrates specific patterns of protein disruption that can be used to predict phenotype severity. The developmental delay in Hyperekplexia, and speech acquisition in particular, may represent failure of developmental neural networks or subtle neurogenic migration defects in the absence of presynaptic glycine release. We recommend early genetic testing for symptomatic neonates and possibly preconception counselling for those at risk for GLRB and SLC6A5 mutations, because of the more challenging phenotype.
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GLRB is the third major gene of effect in Hyperekplexia
Human molecular genetics, 2012Co-Authors: Seo-kyung Chung, Sian-elin Wood, Anna Bode, Rhys H Thomas, Sumimasa Yamashita, Cheney Drew, Thomas D Cushion, Charlotte Hunt, William O. Pickrell, Rita ShiangAbstract:Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, Hyperekplexia. The postsynaptic α(1)-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in Hyperekplexia. Nevertheless, 52% of cases (117 from 232) remain gene negative and unexplained. Ligand-gated heteropentameric GlyRs form chloride ion channels that contain the α(1) and β-subunits (GLRB) in a 2α(1):3β configuration and they form the predominant population of GlyRs in the postnatal and adult human brain, brainstem and spinal cord. We screened GLRB through 117 GLRA1- and SLC6A5-negative Hyperekplexia patients using a multiplex-polymerase chain reaction and Sanger sequencing approach. The screening identified recessive and dominant GLRB variants in 12 unrelated Hyperekplexia probands. This primarily yielded homozygous null mutations, with nonsense (n = 3), small indel (n = 1), a large 95 kb deletion (n = 1), frameshifts (n = 1) and one recurrent splicing variant found in four cases. A further three cases were found with two homozygous and one dominant GLRB missense mutations. We provide strong evidence for the pathogenicity of GLRB mutations using splicing assays, deletion mapping, cell-surface biotinylation, expression studies and molecular modelling. This study describes the definitive assignment of GLRB as the third major gene for Hyperekplexia and impacts on the genetic stratification and biological causation of this neonatal/paediatric disorder. Driven principally by consanguineous homozygosity of GLRB mutations, the study reveals long-term additive phenotypic outcomes for affected cases such as severe apnoea attacks, learning difficulties and developmental delay.
Russell G Snell - One of the best experts on this subject based on the ideXlab platform.
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Hyperekplexia associated with compound heterozygote mutations in the β subunit of the human inhibitory glycine receptor glrb
Human Molecular Genetics, 2002Co-Authors: Mark I. Rees, Trevor M Lewis, John B J Kwok, Geert Mortier, Paul Govaert, Russell G Snell, Peter R Schofield, M OwenAbstract:Hyperekplexia (MIM: 149400) is a neurological disorder characterized by an excessive startle response which can be caused by mutations in the alpha1-subunit (GLRA1) of the heteropentameric human inhibitory glycine receptor (hGlyR). These receptors facilitate fast-response, inhibitory glycinergic neurotransmission in the brainstem and spinal cord leading to a rapid modification and reduction of the excitatory startle response. Mutations in the beta-subunit of GlyR (glrb) occur in a murine model of Hyperekplexia (spastic), but have not been detected in human Hyperekplexia. Following mutation analysis of the human beta-subunit of hGlyR (GLRB) in a cohort of 22 Hyperekplexia patients, we provide evidence to confirm that GLRB mutations can cause human Hyperekplexia. A missense (G920A resulting in G229D) and a splice site mutation (IVS5+5G-->A) occurred together in a compound heterozygote with a transient Hyperekplexia phenotype. Exon trap analysis revealed that IVS5+5G-->A results in the exclusion of exon 5 from GLRB transcripts. Electrophysiological studies showed reduced sensitivity to agonist mediated activation of the alpha1beta (G229D) GlyR suggesting that GlyR beta-subunits are not restricted to conferring modulatory influences and maintaining structural integrity, but may also play a functional role in hGlyR ligand binding.
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Hyperekplexia associated with compound heterozygote mutations in the beta subunit of the human inhibitory glycine receptor glrb
Human Molecular Genetics, 2002Co-Authors: Mark I. Rees, Trevor M Lewis, John B J Kwok, Geert Mortier, Paul Govaert, Russell G Snell, Peter R Schofield, Michael John OwenAbstract:Hyperekplexia (MIM: 149400) is a neurological disorder characterized by an excessive startle response which can be caused by mutations in the alpha1-subunit (GLRA1) of the heteropentameric human inhibitory glycine receptor (hGlyR). These receptors facilitate fast-response, inhibitory glycinergic neurotransmission in the brainstem and spinal cord leading to a rapid modification and reduction of the excitatory startle response. Mutations in the beta-subunit of GlyR (glrb) occur in a murine model of Hyperekplexia (spastic), but have not been detected in human Hyperekplexia. Following mutation analysis of the human beta-subunit of hGlyR (GLRB) in a cohort of 22 Hyperekplexia patients, we provide evidence to confirm that GLRB mutations can cause human Hyperekplexia. A missense (G920A resulting in G229D) and a splice site mutation (IVS5+5G-->A) occurred together in a compound heterozygote with a transient Hyperekplexia phenotype. Exon trap analysis revealed that IVS5+5G-->A results in the exclusion of exon 5 from GLRB transcripts. Electrophysiological studies showed reduced sensitivity to agonist mediated activation of the alpha1beta (G229D) GlyR suggesting that GlyR beta-subunits are not restricted to conferring modulatory influences and maintaining structural integrity, but may also play a functional role in hGlyR ligand binding.
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Compound heterozygosity and nonsense mutations in the α_1-subunit of the inhibitory glycine receptor in Hyperekplexia
Human Genetics, 2001Co-Authors: Mark I. Rees, Trevor M Lewis, Behnaz Vafa, Colin Ferrie, Peter Corry, Fransesco Muntoni, Heinz Jungbluth, John B. Stephenson, Mike Kerr, Russell G SnellAbstract:The α_1-inhibitory glycine receptor is a ligand-gated chloride channel composed of three ligand-binding α_1-subunits and two structural β-subunits that are clustered on the postsynaptic membrane of inhibitory glycinergic neurons. Dominant and recessive mutations in GLRA1 subunits have been associated with a proportion of individuals and families with startle disease or Hyperekplexia (MIM: 149400). Following SSCP and bi-directional di-deoxy fingerprinting mutational analysis of 22 unrelated individuals with Hyperekplexia and Hyperekplexia-related conditions, we report further novel missense mutations and the first nonsense point mutations in GLRA1 , the majority of which localise outside the regions previously associated with dominant, disease-segregating mutations. Population studies reveal the unique association of each mutation with disease, and reveals that a proportion of sporadic Hyperekplexia is accounted for by the homozygous inheritance of recessive GLRA1 mutations or as part of a compound heterozygote.
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Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in Hyperekplexia
Human genetics, 2001Co-Authors: Mark I. Rees, Trevor M Lewis, Behnaz Vafa, Colin Ferrie, Peter Corry, Fransesco Muntoni, Heinz Jungbluth, John B. Stephenson, Michael Patrick Kerr, Russell G SnellAbstract:The α1-inhibitory glycine receptor is a ligand-gated chloride channel composed of three ligand-binding α1-subunits and two structural β-subunits that are clustered on the postsynaptic membrane of inhibitory glycinergic neurons. Dominant and recessive mutations in GLRA1 subunits have been associated with a proportion of individuals and families with startle disease or Hyperekplexia (MIM: 149400). Following SSCP and bi-directional di-deoxy fingerprinting mutational analysis of 22 unrelated individuals with Hyperekplexia and Hyperekplexia-related conditions, we report further novel missense mutations and the first nonsense point mutations in GLRA1, the majority of which localise outside the regions previously associated with dominant, disease-segregating mutations. Population studies reveal the unique association of each mutation with disease, and reveals that a proportion of sporadic Hyperekplexia is accounted for by the homozygous inheritance of recessive GLRA1 mutations or as part of a compound heterozygote.