scholarly journals Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission

Brain ◽  
2019 ◽  
Vol 143 (2) ◽  
pp. 441-451 ◽  
Author(s):  
Hanna C A Lammertse ◽  
Annemiek A van Berkel ◽  
Michele Iacomino ◽  
Ruud F Toonen ◽  
Pasquale Striano ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Synaptic Transmission ◽  
Protein Stability ◽  
Developmental Delay ◽  
Fold Increase ◽  
Null Mouse ◽  
Gain Of Function ◽  
Gene Encoding ◽  
Cellular Effects ◽  
Protein Levels

Abstract Heterozygous mutations in the STXBP1 gene encoding the presynaptic protein MUNC18-1 cause STXBP1 encephalopathy, characterized by developmental delay, intellectual disability and epilepsy. Impaired mutant protein stability leading to reduced synaptic transmission is considered the main underlying pathogenetic mechanism. Here, we report the first two cases carrying a homozygous STXBP1 mutation, where their heterozygous siblings and mother are asymptomatic. Both cases were diagnosed with Lennox-Gastaut syndrome. In Munc18-1 null mouse neurons, protein stability of the disease variant (L446F) is less dramatically affected than previously observed for heterozygous disease mutants. Neurons expressing Munc18L446F showed minor changes in morphology and synapse density. However, patch clamp recordings demonstrated that L446F causes a 2-fold increase in evoked synaptic transmission. Conversely, paired pulse plasticity was reduced and recovery after stimulus trains also. Spontaneous release frequency and amplitude, the readily releasable vesicle pool and the kinetics of short-term plasticity were all normal. Hence, the homozygous L446F mutation causes a gain-of-function phenotype regarding release probability and synaptic transmission while having less impact on protein levels than previously reported (heterozygous) mutations. These data show that STXBP1 mutations produce divergent cellular effects, resulting in different clinical features, while sharing the overarching encephalopathic phenotype (developmental delay, intellectual disability and epilepsy).

Sulfonylurea-insensitive permanent neonatal diabetes caused by a severe gain-of-function Tyr330His substitution in Kir6.2

2022 ◽  
Author(s):  
Conor McClenaghan ◽  
Novella Rapini ◽  
Domenico Umberto De Rose ◽  
Jian Gao ◽  
Jacob Roeglin ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Molecular Basis ◽  
Glucose Monitoring ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Gain Of Function ◽  
Gene Encoding ◽  
Permanent Neonatal Diabetes ◽  
Mild Developmental Delay ◽  
Atp Inhibition

Background/Aims: Mutations in KCNJ11, the gene encoding the Kir6.2 subunit of pancreatic and neuronal KATP channels, are associated with a spectrum of neonatal diabetes diseases. Methods: Variant screening was used to identify cause of neonatal diabetes, and continuous glucose monitoring used to assess effectiveness of sulfonylurea treatment. Electrophysiological analysis of variant KATP channel function was used to determine molecular basis. Results: We identified a previously uncharacterized KCNJ11 mutation, c.988T>C [pTyr330His], in an Italian child diagnosed with sulfonylurea-resistant permanent neonatal diabetes and developmental delay (iDEND). Functional analysis of recombinant KATP channels reveals that this mutation causes a drastic gain-of-function, due to a reduction in ATP-inhibition. Further, we demonstrate that the Tyr330His substitution causes a significant decrease in sensitivity to the sulfonylurea, glibenclamide. Conclusions: In this subject, the KCNJ11(c.988T>C) mutation provoked neonatal diabetes, with mild developmental delay, which was insensitive to correction by sulfonylurea therapy. This is explained by the molecular loss of sulfonylurea sensitivity conferred by the Tyr330His substitution, and highlights the need for molecular analysis of such mutations.

scholarly journals Calcium channelopathies and intellectual disability: a systematic review

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Miriam Kessi ◽  
Baiyu Chen ◽  
Jing Peng ◽  
Fangling Yan ◽  
Lifen Yang ◽  
...  
Keyword(s):  
Systematic Review ◽  
Intellectual Disability ◽  
Calcium Channel ◽  
Developmental Delay ◽  
Cerebellar Atrophy ◽  
Dominant Negative ◽  
Main Body ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Gain And Loss

Abstract Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

scholarly journals Isolated Erythrocytosis Associated With 3 Novel Missense Mutations in the EGLN1 Gene

2020 ◽  
Vol 8 ◽  
pp. 232470962094725
Author(s):  
Joseph A. Moore ◽  
Maimon E. Hubbi ◽  
Chenliang Wang ◽  
Yingfei Wang ◽  
Weibo Luo ◽  
...  
Keyword(s):  
Protein Stability ◽  
Cultured Cells ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Missense Mutations ◽  
Novel Mutations ◽  
Gene Encoding ◽  
Protein Levels ◽  
Hypoxia Inducible Factor 1 ◽  
Prolyl Hydroxylase Domain

Hypoxia-inducible factor-1 (HIF-1) is a key regulator of erythropoiesis. In this article, we report 3 novel mutations, P378S, A385T, and G206C, on the EGLN1 gene encoding the negative HIF-1α regulator prolyl hydroxylase domain-2 (PHD2) in 3 patients with isolated erythrocytosis. These mutations impair PHD2 protein stability and partially reduce PHD2 activity, leading to increased HIF-1α protein levels in cultured cells.

Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2339-2344 ◽  
Author(s):  
Kazunobu Kato ◽  
Constantino Martinez ◽  
Susan Russell ◽  
Paquita Nurden ◽  
Alan Nurden ◽  
...  
Keyword(s):  
Fold Increase ◽  
Granule Size ◽  
Platelet Glycoprotein ◽  
Severe Bleeding ◽  
Gene Encoding ◽  
Protein Levels ◽  
Transmission Electron ◽  
Presynaptic Protein ◽  
Bernard Soulier Syndrome

Abstract Here we report the characterization of a mouse model of the Bernard-Soulier syndrome generated by a targeted disruption of the gene encoding the glycoprotein (GP) Ibβ subunit of the GP Ib-IX complex. Similar to a Bernard-Soulier model generated by disruption of the mouse GP Ibα subunit, GP IbβNull mice display macrothrombocytopenia and a severe bleeding phenotype. When examined by transmission electron microscopy, the large platelets produced by a GP IbβNull genotype revealed α-granules with increased size as compared with the α-granules from control mouse platelets. Data are presented linking the overexpression of a septin protein, SEPT5, to the presence of larger α-granules in the GP IbβNull platelet. The SEPT5 gene resides approximately 250 nucleotides 5′ to the GP Ibβ gene and has been associated with modulating exocytosis from neurons and platelets as part of a presynaptic protein complex. Fusion mRNA transcripts present in megakaryocytes can contain both the SEPT5 and GP Ibβ coding sequences as a result in an imperfect polyadenylation signal within the 3′ end of both the human and mouse SEPT5 genes. We observed a 2- to 3-fold increase in SEPT5 protein levels in platelets from GP IbβNull mice. These results implicate SEPT5 levels in the maintenance of normal α-granule size and may explain the variant granules associated with human GP Ibβ mutations and the Bernard-Soulier syndrome.

scholarly journals Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Nathan L Absalom ◽  
Vivian W Y Liao ◽  
Kavitha Kothur ◽  
Dinesh C Indurthi ◽  
Bruce Bennetts ◽  
...  
Keyword(s):  
De Novo ◽  
Drug Effects ◽  
Receptor Expression ◽  
Aminobutyric Acid ◽  
Loss Of Function ◽  
Molecular Phenotype ◽  
Gain Of Function ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Receptor Phenotype

Abstract Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants.

Zoledronic acid modulates osteoclast apoptosis through activation of the NF-κB signaling pathway in ovariectomized rats

2021 ◽  
pp. 153537022110110
Author(s):  
Yu-Ting Cheng ◽  
Jian Liao ◽  
Qian Zhou ◽  
Hua Huo ◽  
Lucas Zellmer ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Bone Mass ◽  
Mass Loss ◽  
Ovariectomized Rats ◽  
Therapeutic Effects ◽  
Bone Mass Loss ◽  
Cellular Effects ◽  
Protein Levels ◽  
Adverse Factor ◽  
Osteoclast Apoptosis

Bone mass loss (osteoporosis) seen in postmenopausal women is an adverse factor for implant denture. Using an ovariectomized rat model, we studied the mechanism of estrogen-deficiency-caused bone loss and the therapeutic effect of Zoledronic acid. We observed that ovariectomized-caused resorption of bone tissue in the mandible was evident at four weeks and had not fully recovered by 12 weeks post-ovariectomized compared with the sham-operated controls. Further evaluation with a TUNEL assay showed ovariectomized enhanced apoptosis of osteoblasts but inhibited apoptosis of osteoclasts in the mandible. Zoledronic acid given subcutaneously as a single low dose was shown to counteract both of these ovariectomized effects. Immunohistochemical staining showed that ovariectomized induced the protein levels of RANKL and the 65-kD subunit of the NF-κB complex mainly in osteoclasts, as confirmed by staining for TRAP, a marker for osteoclasts, whereas zoledronic acid inhibited these inductions. Western blotting showed that the levels of RANKL, p65, as well as the phosphorylated form of p65, and IκB-α were all higher in the ovariectomized group than in the sham and ovariectomized + zoledronic acid groups at both the 4th- and 12th-week time points in the mandible. These data collectively suggest that ovariectomized causes bone mass loss by enhancing apoptosis of osteoblasts and inhibiting apoptosis of osteoclasts. In osteoclasts, these cellular effects may be achieved by activating RANKL-NF-κB signalling. Moreover, zoledronic acid elicits its therapeutic effects in the mandible by counteracting these cellular and molecular consequences of ovariectomized.

scholarly journals Cerebrovascular diseases in two patients with entire NSD1 deletion

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Toshiyuki Itai ◽  
Satoko Miyatake ◽  
Taku Hatano ◽  
Nobutaka Hattori ◽  
Atsuko Ohno ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Brain Imaging ◽  
Developmental Delay ◽  
Movement Disorders ◽  
Subdural Hematoma ◽  
Early Onset ◽  
Cerebrovascular Diseases ◽  
Brain Contusion ◽  
Abnormal Gait

AbstractWe describe two patients with NSD1 deletion, who presented with early-onset, or recurrent cerebrovascular diseases (CVDs). A 39-year-old female showed developmental delay and abnormal gait in infancy, and developed slowly-progressive intellectual disability and movement disorders. Brain imaging suggested recurrent parenchymal hemorrhages. A 6-year-old male had tremor as a neonate and brain imaging revealed subdural hematoma and brain contusion. This report suggests possible involvement of CVDs associated with NSD1 deletion.

scholarly journals Clinical performance of the CytoScan Dx Assay in diagnosing developmental delay/intellectual disability

2015 ◽  
Vol 18 (2) ◽  
pp. 168-173 ◽  
Author(s):  
Rolph Pfundt ◽  
Kat Kwiatkowski ◽  
Alan Roter ◽  
Anju Shukla ◽  
Eric Thorland ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Clinical Performance
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