Novel mutation in <i>GLRB</i> in a large family with hereditary hyperekplexia

Çolak, Dilek; Al-Bakheet, Albandary; Al‐Hashmi, Nadia; Shuaib, Taghreed; Al-Hemidan, Amal; Aldhalaan, Hesham; Rahbeeni, Zuhair; AlSayed, Moeenaldeen; Al-Younes, Banan; Ozand, PT; Kaya, Namik

doi:10.1111/j.1399-0004.2011.01661.x

Cited by 34 publications

(25 citation statements)

References 10 publications

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“…8,9 This disorder has been described as an autosomal recessive disorder and haploinsufficiency was excluded as possible cause. 8,9 We assume that the partial deletion of GLRB itself does not have a major impact on the patient's ID, because no other mutations were found in this gene and no ID is described in patients with mutations in one or both allels of GLRB.…”

Section: Discussionmentioning

confidence: 99%

Partial deletion of GLRB and GRIA2 in a patient with intellectual disability

et al. 2012

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We report about the partial de novo loss of GLRB and GRIA2 in an individual with intellectual disability (ID). No additional mutations were found in either gene. GLRB itself does not seem to be a good candidate as it causes autosomal recessive hyperekplexia and no symptoms were found in the patient. Mutations of GRIA2 have not been described as cause of ID to date. Nonetheless, it is a very attractive candidate because it encodes a subunit of a glutamate receptor, which is highly expressed in postsynaptic structures and has an important role in signal transduction across synapses. Although we were able to isolate a fragment of a fusion transcript of both genes from the patient's blood, we were not able to isolate a transcript with an open reading frame throughout the entire length. The reading frame could be restored by differential splicing, which might take place in brain tissue but not in blood. We assume that either haploinsufficiency of GRIA2 or a GLRB/GRIA2 fusion gene leading to a protein with dominant-negative properties is causing the phenotype of the patient.

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Section: Discussionmentioning

confidence: 99%

Partial deletion of GLRB and GRIA2 in a patient with intellectual disability

et al. 2012

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“…On the translational level, the phenotype is confirmed by the spastic mouse (featuring a substantial reduction of Glrb), which is characterized by an increased startle reaction 62 . While, in humans, startle symptoms may diminish with age, (agora-) phobic behavior may become a more prominent clinical feature 63,64 .…”

Section: Discussionmentioning

confidence: 99%

GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder

et al. 2017

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The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG -related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1,370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, p=3.3x10 -8 ; rs191260602, p=3.9x10 -8 ). We followed up on this finding in a larger dimensional ACQ sample (N=2,547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3,845) and a casecontrol sample with the categorical phenotype PD/AG (N combined =1,012) obtaining highly Partial Glrb knockout-mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, though functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

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“…Some of these mutations have been found to affect GlyR intracellular trafficking rather than agonist binding or channel gating (69,98). Consistent with an important role of the ␤ subunit in postsynaptic GlyR function, mutations in the GLRB gene have been associated with HKPX2 (97,99). A third major form of hyperekplexia of presynaptic origin (HKPX3) is due to mutations in the gene encoding the neuronal glycine transporter GlyT2 (SLC6A5) (97).…”

Section: Mutations In Human Glyr Genes Cause Hyperekplexiamentioning

confidence: 99%

Inhibitory Glycine Receptors: An Update

Dutertre

Becker

Betz

2012

Journal of Biological Chemistry

164

134

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Strychnine-sensitive glycine receptors (GlyRs) mediate synaptic inhibition in the spinal cord, brainstem, and other regions of the mammalian central nervous system. In this minireview, we summarize our current view of the structure, ligand-binding sites, and chloride channel of these receptors and discuss recently emerging functions of distinct GlyR isoforms. GlyRs not only regulate the excitability of motor and afferent sensory neurons, including pain fibers, but also are involved in the processing of visual and auditory signals. Hence, GlyRs constitute promising targets for the development of therapeutically useful compounds.The normal functioning of the CNS depends on the balanced interplay of both excitatory and inhibitory neurons. Glutamate is the principal excitatory and GABA and glycine are the major inhibitory neurotransmitters in the adult mammalian CNS. Glycine serves, in addition, as a co-agonist of glutamate at the NMDA subtype of excitatory glutamate receptors.Glycinergic synapses mediate fast inhibitory neurotransmission mainly in the spinal cord, brainstem, and caudal brain and control a variety of motor and sensory functions, including vision and audition (1). Glycine exerts its inhibitory effects via specific glycine receptors (GlyRs) 2 that are highly enriched in the postsynaptic membrane. Binding of glycine leads to the opening of the GlyR integral anion channel, and the resulting influx of Cl Ϫ ions hyperpolarizes the postsynaptic cell, thereby inhibiting neuronal firing. The alkaloid strychnine antagonizes glycine binding with high affinity and has proven to be a unique tool in radioligand binding studies (2) and affinity purification (3) of GlyRs. Since these original studies, three decades of GlyR research have generated a wealth of genetic, functional, and structural data, which are summarized here.

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Novel mutation in GLRB in a large family with hereditary hyperekplexia

Cited by 34 publications

References 10 publications

Partial deletion of GLRB and GRIA2 in a patient with intellectual disability

Partial deletion of GLRB and GRIA2 in a patient with intellectual disability

GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder

Inhibitory Glycine Receptors: An Update

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