Denaturing high-performance liquid chromatography screening of the long QT syndrome-related cardiac sodium and potassium channel genes and identification of novel mutations and single nucleotide polymorphisms

Lai, Ling‐Ping; Su, Yi Ning; Chiang, Fu-Tien; Juang, Jyh-Ming Jimmy; Liu, Yen‐Bin; Ho, Yi‐Lwun; Chen, Wen‐Jone; Yeh, San Jou; Wang, Chun Chieh; Ko, Yu‐Lin; Wu, Tsu Juey; Ueng, Kwo Chang; Miao, Lei; Tsao, Hsuan Ming; Chen, Shih Ann; Lin, Tin Kwang; Wu, Mei; Lo, Huey‐Ming; Huang, Shoei K. Stephen; Lin, Jiunn Lee

doi:10.1007/s10038-005-0283-3

Cited by 40 publications

(21 citation statements)

References 30 publications

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“…3 Confocal laser scanning microscope: heterozygote expression in twin's heart shows a nearly 50% reduction in Na + channels expression (orange punctate positiveness) in ventricular myocytes in respect to control case type III and Brugada syndrome, which can lead to sudden cardiac death. Differential expression and localization of sodium channel subunits are likely to be important determinants of electric excitability of cardiac myocytes [11,13,19,25]. Cardiac ion channel genes, particularly SCN5A, have been hypothesized as candidate gene(s) for SIDS [29].…”

Section: Discussionmentioning

confidence: 99%

Heterozygous nonsense SCN5A mutation W822X explains a simultaneous sudden infant death syndrome

et al. 2008

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The sudden, unexpected, and unexplained death of both members of a set of healthy twins (simultaneous sudden infant death syndrome (SSIDS)) is defined as a case in which both infants meet the definition of sudden infant death syndrome individually. A search of the world medical literature resulted in only 42 reported cases of SSIDS. We report the case of a pair of identical, male, monozygotic twins, 138 days old, who suddenly died, meeting the full criteria of SSIDS and where a genetic screen was performed, resulting in a heterozygous nonsense SCN5A mutation (W822X) in both twins. Immunohistochemistry was performed on cardiac tissue samples utilizing polyclonal antibodies anti-Na+ CP type Valpha (C-20) and a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. The cellular localization of the Na+ CP type Valpha (C-20) demonstrated by confocal microscopy on staining pattern of myocytes was concentrated in the intercalated disks of ventricular myocytes. These findings suggest that defective ion channels represent viable candidates for the pathogenesis of SIDS and, obviously, of SSIDS, supporting a link between sudden infant death syndrome and cardiac channelopathies.

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Section: Discussionmentioning

confidence: 99%

Heterozygous nonsense SCN5A mutation W822X explains a simultaneous sudden infant death syndrome

et al. 2008

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“…We do not attempt to obtain the best fit to all of our data, because there are most likely several sets of parameters that will generate similar simulations from the limited type of data. This model has to be further tested with more extensive voltage clamp protocols and constructs with linked subunit, as in our earlier work on KCNQ1 channels and KCNQ1/KCNE1 channels (33,42), to generate a unique set of parameters. However, we here show that a model based on our conclusion that KCNE3 affects KCNQ1 by shifting the S4 movement −100 mV is able to replicate our data.…”

Section: Kcne3 Shifts the Equilibrium Of S4 Movement And Gate Opening Tomentioning

confidence: 99%

KCNE3 acts by promoting voltage sensor activation in KCNQ1

Barro-Soria

Perez

Larsson

2015

Proc. Natl. Acad. Sci. U.S.A.

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KCNE β-subunits assemble with and modulate the properties of voltage-gated K + channels. In the colon, stomach, and kidney, KCNE3 coassembles with the α-subunit KCNQ1 to form K + channels important for K + and Cl − secretion that appear to be voltageindependent. How KCNE3 subunits turn voltage-gated KCNQ1 channels into apparent voltage-independent KCNQ1/KCNE3 channels is not completely understood. Different mechanisms have been proposed to explain the effect of KCNE3 on KCNQ1 channels. Here, we use voltage clamp fluorometry to determine how KCNE3 affects the voltage sensor S4 and the gate of KCNQ1. We find that S4 moves in KCNQ1/KCNE3 channels, and that inward S4 movement closes the channel gate. However, KCNE3 shifts the voltage dependence of S4 movement to extreme hyperpolarized potentials, such that in the physiological voltage range, the channel is constitutively conducting. By separating S4 movement and gate opening, either by a mutation or PIP 2 depletion, we show that KCNE3 directly affects the S4 movement in KCNQ1. Two negatively charged residues of KCNE3 (D54 and D55) are found essential for the effect of KCNE3 on KCNQ1 channels, mainly exerting their effects by an electrostatic interaction with R228 in S4. Our results suggest that KCNE3 primarily affects the voltage-sensing domain and only indirectly affects the gate.proteins with a variety of crucial physiological roles. Most Kv channels are expressed in excitable cells where, e.g., they regulate and modulate the resting potential and the threshold and duration of the action potential (1). The KCNQ1 channel (also called Kv7.1 or KvLQT1) differs from most other Kv channels in that it has key physiological roles in both excitable cells, such as cardiomyocytes (2, 3) and pancreatic β-cells (4, 5), and in nonexcitable cells, such as in epithelia (3, 6). The KCNQ1 channels display diverse biophysical properties in different cell types, a diversity thought to be mainly due to the KCNQ1 channel's association with five tissue-specific, single-transmembrane segment KCNE β-subunits (KCNE1-5) (7-13). KCNQ1 α-subunit expressed by itself forms a voltage-dependent K + channel that opens at negative voltages ( Fig. 1 A and D). However, coexpression of KCNQ1 with KCNE1 slows the kinetics of activation and shifts the voltage dependence of activation to positive voltages ( Fig. 1 B and D) (7, 8), thereby generating the slowly activating, voltage-dependent I Ks current that controls the repolarization phase of cardiac action potentials. In contrast, coexpression of KCNQ1 with KCNE3 results in a constitutively conducting channel in the physiological voltage range of -80 to +40 mV ( Fig. 1 C and D), which is important for transport of water and salt in epithelial tissues, including those of the colon, small intestine, and airways (9,14,15). In addition, mutations of KCNE3 have been associated with cardiac arrhythmia (16,17) and diseases in the inner ear, such as Meniere's disease and tinnitus (18,19). Because KCNQ1/KCNE3 channels are necessary for water and salt secretion...

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“…Effective methods for mutation screening in the coding region of SCN5A using CAE-SSCP [Hofman-Bang et al, 2006], DHPLC [Lai et al, 2005;Ning et al, 2003], or Melting Curve Analysis [Millat et al, 2009] have been described. Irrespective of the method used, it is important that the sensitivity and specificity of the method used is validated in the implementing laboratory [Jespersgaard et al, 2006].…”

Section: Brs1-mutations In Scn5amentioning

confidence: 99%

The genetic basis of Brugada syndrome: A mutation update

et al. 2009

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Brugada syndrome (BrS) is a condition characterized by a distinct ST-segment elevation in the right precordial leads of the electrocardiogram and, clinically, by an increased risk of cardiac arrhythmia and sudden death. The condition predominantly exhibits an autosomal dominant pattern of inheritance with an average prevalence of 5:10,000 worldwide. Currently, more than 100 mutations in seven genes have been associated with BrS. Loss-of-function mutations in SCN5A, which encodes the a-subunit of the Na v 1.5 sodium ion channel conducting the depolarizing I Na current, causes 15-20% of BrS cases. A few mutations have been described in GPD1L, which encodes glycerol-3-phosphate dehydrogenase-1 like protein; CACNA1C, which encodes the a-subunit of the Ca v 1.2 ion channel conducting the depolarizing I L,Ca current; CACNB2, which encodes the stimulating b2-subunit of the Ca v 1.2 ion channel; SCN1B and SCN3B, which, in the heart, encodes b-subunits of the Na v 1.5 sodium ion channel, and KCNE3, which encodes the ancillary inhibitory b-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium I to current. BrS exhibits variable expressivity, reduced penetrance, and ''mixed phenotypes,'' where families contain members with BrS as well as long QT syndrome, atrial fibrillation, short QT syndrome, conduction disease, or structural heart disease, have also been described.

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Denaturing high-performance liquid chromatography screening of the long QT syndrome-related cardiac sodium and potassium channel genes and identification of novel mutations and single nucleotide polymorphisms

Cited by 40 publications

References 30 publications

Heterozygous nonsense SCN5A mutation W822X explains a simultaneous sudden infant death syndrome

Heterozygous nonsense SCN5A mutation W822X explains a simultaneous sudden infant death syndrome

KCNE3 acts by promoting voltage sensor activation in KCNQ1

The genetic basis of Brugada syndrome: A mutation update

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