42 research outputs found
The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs.
SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T>C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies
Synergistic interplay of Gβγ and phosphatidylinositol 4,5-bisphosphate dictates Kv7.4 channel activity.
Kv7.4 channels are key determinants of arterial contractility and cochlear mechanosensation that, like all Kv7 channels, have an obligatory requirement for phosphatidylinositol 4,5-bisphosphate (PIP2). βγ G proteins (Gβγ) have been identified as novel positive regulators of Kv7.4. The present study ascertained whether Gβγ increased Kv7.4 open probability through an increased sensitivity to PIP2. In HEK cells stably expressing Kv7.4, PIP2 or Gβγ increased open probability in a concentration dependent manner. Depleting PIP2 prevented any Gβγ-mediated stimulation whilst an array of Gβγ inhibitors prohibited any PIP2-induced current enhancement. A combination of PIP2 and Gβγ at sub-efficacious concentrations increased channel open probability considerably. The stimulatory effects of three Kv7.2-7.5 channel activators were also lost by PIP2 depletion or Gβγ inhibitors. This study alters substantially our understanding of the fundamental processes that dictate Kv7.4 activity, revealing a more complex and subtle paradigm where the reliance on local phosphoinositide is dictated by interaction with Gβγ
Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.</p
Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels
Employing state-of-the-art technology to explore mechanisms of epilepsy and novel therapeutic options
Transplanted immature projection neurons maintain their molecular subtype identity and re-establish appropriate long distance connectivity within the postnatal mouse CNS
Human cortical tissue obtained from epilepsy surgery as a model system to explore pathophysiological mechanisms underlying epilepsy and drug resistance
GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak
Paroxysmal dyskinesias are episodic movement disorders that can be inherited or are sporadic in nature.
The pathophysiology underlying these disorders remains largely unknown but may involve disrupted ion
homeostasis due to defects in cell-surface channels or nutrient transporters. In this study, we describe a family
with paroxysmal exertion-induced dyskinesia (PED) over 3 generations. Their PED was accompanied by
epilepsy, mild developmental delay, reduced CSF glucose levels, hemolytic anemia with echinocytosis, and
altered erythrocyte ion concentrations. Using a candidate gene approach, we identified a causative deletion
of 4 highly conserved amino acids (Q282_S285del) in the pore region of the glucose transporter 1 (GLUT1).
Functional studies in Xenopus oocytes and human erythrocytes revealed that this mutation decreased glucose
transport and caused a cation leak that alters intracellular concentrations of sodium, potassium, and calcium.
We screened 4 additional families, in which PED is combined with epilepsy, developmental delay, or migraine,
but not with hemolysis or echinocytosis, and identified 2 additional GLUT1 mutations (A275T, G314S) that
decreased glucose transport but did not affect cation permeability. Combining these data with brain imaging
studies, we propose that the dyskinesias result from an exertion-induced energy deficit that may cause episodic
dysfunction of the basal ganglia, and that the hemolysis with echinocytosis may result from alterations in
intracellular electrolytes caused by a cation leak through mutant GLUT1