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Query: UMLS:C0022104 (
irritable bowel syndrome
)
8,033
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The
SCN5A
-encoded Na(v)1.5 Na(+) channel is expressed in interstitial cells of Cajal and smooth muscle in the circular layer of the human intestine. Patients with mutations in
SCN5A
are more likely to report gastrointestinal symptoms, especially abdominal pain. Twin and family studies of
irritable bowel syndrome
(
IBS
) suggest a genetic basis for
IBS
, but no genes have been identified to date. Therefore, our aims were to evaluate
SCN5A
as a candidate gene involved in the pathogenesis of
IBS
and to determine physiological consequences of identified mutations. Mutational analysis was performed on genomic DNA obtained from 49 subjects diagnosed with
IBS
who reported at least moderately severe abdominal pain. One patient hosted a loss-of-function missense mutation, G298S, that was not observed in >3,000 reference alleles derived from 1,500 healthy control subjects. Na(+) currents were recorded from the four common human
SCN5A
transcripts in transfected HEK-293 cells. Comparing Na(v)1.5 with G298S-
SCN5A
versus wild type in HEK cells, Na(+) current density was significantly less by 49-77%, and channel activation time was delayed in backgrounds that also contained the common H558R polymorphism. Single-channel measurements showed no change in Na(v)1.5 conductance. Mechanosensitivity was reduced in the H558/Q1077del transcript but not in the other three backgrounds. In conclusion, the G298S-
SCN5A
missense mutation caused a marked reduction of whole cell Na(+) current and loss of function of Na(v)1.5, suggesting
SCN5A
as a candidate gene in the pathophysiology of
IBS
.
...
PMID:Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy. 1905 59
Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and
irritable bowel syndrome
. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has emerged based on channel variants that alter regulation by intracellular signaling or cytoskeletal proteins. Fibroblast growth factor homologous factors (FHFs) are a family of intracellular signaling proteins linked with Nav channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Nav channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in
SCN5A
(encodes primary cardiac Nav channel Nav1.5) that alter FHF binding result in human cardiovascular disease. We describe a five*generation kindred with a history of atrial and ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Affected family members harbor a novel
SCN5A
variant resulting in p.H1849R. p.H1849R is localized in the central binding core on Nav1.5 for FHFs. Consistent with these data, Nav1.5 p.H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Nav1.5 p.H1849R as a gain-of-function for INa by altering steady-state inactivation and slowing the rate of Nav1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Nav1.5 p.H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins.
...
PMID:SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia. 2639 62
In the gastrointestinal (GI) tract, abnormalities in secretion, absorption, motility, and sensation have been implicated in functional gastrointestinal disorders (FGIDs). Ion channels play important roles in all these GI functions. Disruptions of ion channels' ability to conduct ions can lead to diseases called ion channelopathies. Channelopathies can result from changes in ion channel biophysical function or expression due to mutations, posttranslational modification, and accessory protein malfunction. Channelopathies are strongly established in the fields of cardiology and neurology, but ion channelopathies are only beginning to be recognized in gastroenterology. In this review, we describe the state of the emerging field of GI ion channelopathies. Several recent discoveries show that channelopathies result in alterations in GI motility, secretion, and sensation. In the epithelium, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) or CFTR-associating proteins result in channelopathies with constipation or diarrhea as phenotypes. In the muscle, mutations in the
SCN5A
-encoded voltage-gated sodium channel Na
V
1.5 are associated with
irritable bowel syndrome
. In the sensory nerves, channelopathies of voltage-gated sodium channels Na
V
1.7 and Na
V
1.9 (encoded by SCN9A, SCN11A, respectively) manifest by either GI hyper- or hyposensation. Recent advances in structural biology and ion channel biophysics, coupled with personalized medicine, have fueled rapid discoveries of novel channelopathies and direct drug targeting of specific channelopathies. In summary, the emerging field of GI ion channelopathies has significant implications for functional GI disease stratification, diagnosis, and treatment.
...
PMID:Ion channelopathies in functional GI disorders. 2751 80
Traditionally,
irritable bowel syndrome
has been considered to be a disorder with no known underlying structural or biochemical explanation, but this concept is likely to be outdated. In this Review we challenge the widely accepted view that
irritable bowel syndrome
is an unexplained brain-gut disorder. There is epidemiological evidence that, in a major subset of patients, gastrointestinal symptoms arise first and only later do incident mood disorders occur. Additionally, possible mechanisms for gut-brain dysfunction have been identified, suggesting primary gut disturbances might be the underlying cause in a subgroup. Underlying mechanisms that could lead to
irritable bowel syndrome
include genetic factors (most notably an identified mutation of
SCN5A
); post-infectious changes, chronic infections and disturbances in the intestinal microbiota; low-grade mucosal inflammation, immune activation, and altered intestinal permeability; disordered bile salt metabolism (in 10-20% of cases with diarrhoea); abnormalities in serotonin metabolism; and alterations in brain function, which could be primary or secondary factors. Identical
irritable bowel syndrome
symptoms are probably due to different disease processes; grouping patients with this disorder into either diarrhoea-predominant or constipation-predominant subtypes promotes heterogeneity. An approach based on the underlying pathophysiology could help to develop therapies that target causes and ultimately provide a cure for patients with
irritable bowel syndrome
.
...
PMID:Pathophysiology of irritable bowel syndrome. 2840 70
The
SCN5A
-encoded voltage-gated mechanosensitive Na
+
channel Na
V
1.5 is expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal. Na
V
1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominantly Caucasian
irritable bowel syndrome
(
IBS
) patient cohorts, 2-3% of patients have
SCN5A
missense mutations that alter Na
V
1.5 function and may contribute to
IBS
pathophysiology. In this study we examined a racially and ethnically diverse cohort of
IBS
patients for
SCN5A
missense mutations, compared them with
IBS
-negative controls, and determined the resulting Na
V
1.5 voltage-dependent and mechanosensitive properties. All
SCN5A
exons were sequenced from somatic DNA of 252 Rome III
IBS
patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type
SCN5A
by site-directed mutagenesis and cotransfected with green fluorescent protein into HEK-293 cells. Na
V
1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 (2.0%)
IBS
patients had six rare
SCN5A
mutations that were absent in 377
IBS
-negative controls. Six of six (100%)
IBS
-associated Na
V
1.5 mutations had voltage-dependent gating abnormalities [current density reduction (R225W, R433C, R986Q, and F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, and F1293S)], and at least one kinetic parameter was altered in all mutations. Four of six (67%)
IBS
-associated
SCN5A
mutations (R225W, R433C, R986Q, and F1293S) resulted in altered Na
V
1.5 mechanosensitivity. In this racially and ethnically diverse cohort of
IBS
patients, we show that 2% of
IBS
patients harbor
SCN5A
mutations that are absent in
IBS
-negative controls and result in Na
V
1.5 channels with abnormal voltage-dependent and mechanosensitive function. NEW & NOTEWORTHY The voltage-gated Na
+
channel Na
V
1.5 contributes to smooth muscle physiology and electrical slow waves. In a racially and ethnically mixed
irritable bowel syndrome
cohort, 2% had mutations in the Na
V
1.5 gene
SCN5A
. These mutations were absent in
irritable bowel syndrome
-negative controls. Most mutant Na
V
1.5 channels were loss of function in voltage dependence or mechanosensitivity.
...
PMID:Irritable bowel syndrome patients have SCN5A channelopathies that lead to decreased Na
V
1.5 current and mechanosensitivity. 2916 13
SCN5A
is expressed in cardiomyocytes and gastrointestinal (GI) smooth muscle cells (SMCs) as the voltage-gated mechanosensitive sodium channel Na
V
1.5. The influx of Na
+
through Na
V
1.5 produces a fast depolarization in membrane potential, indispensable for electrical excitability in cardiomyocytes and important for electrical slow waves in GI smooth muscle. As such, abnormal Na
V
1.5 voltage gating or mechanosensitivity may result in channelopathies.
SCN5A
mutation G615E - found separately in cases of acquired long-QT syndrome, sudden cardiac death, and
irritable bowel syndrome
- has a relatively minor effect on Na
V
1.5 voltage gating. The aim of this study was to test whether G615E impacts mechanosensitivity. Mechanosensitivity of wild-type (WT) or G615E-Na
V
1.5 in HEK-293 cells was examined by shear stress on voltage- or current-clamped whole cells or pressure on macroscopic patches. Unlike WT, voltage-clamped G615E-Na
V
1.5 showed a loss in shear- and pressure-sensitivity of peak current yet a normal leftward shift in the voltage-dependence of activation. In current-clamp, shear stress led to a significant increase in firing spike frequency with a decrease in firing threshold for WT but not G615E-Na
V
1.5. Our results show that the G615E mutation leads to functionally abnormal Na
V
1.5 channels, which cause disruptions in mechanosensitivity and mechano-electrical feedback and suggest a potential contribution to smooth muscle pathophysiology.
...
PMID:
SCN5A
mutation G615E results in Na
V
1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity. 3126 9
