Long QT syndrome ... (Long QT syndrome - LQTS-) - Genes KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CPVT1, CAV3, KCNJ5, CACNA1C and SCN4B.
This syndrome by a history of episodes of syncope and the presence of an abnormal duration of QT interval on the ECG is characterized, sometimes resulting in sudden death due to ventricular paroxysmal arrhythmia. Autosomal dominant form is called Romano-Ward syndrome. The autosomal recessive form called Jervell-Lange-Nielsen syndrome.
Several genotypes of long QT syndrome (LQTS: Long QT Syndromes). These syndromes correspond to cardiac ion channelopathies characterized by congenital abnormalities of cardiac repolarization causing syncope and sudden death in 50% of untreated patients 10 years of evolution. In these patients an increase electrocardiographic QT interval is always observed.
These syndromes have been associated with mutations of 13 genes that are involved in the development of sodium and potassium channels and their regulatory subunits. Despite being found in many genes mutations, the etiology of the syndrome remains unknown in 30 to 40% of cases.
Each of the variants of LQT syndrome (Long QT Syndrome) has become associated to mutations that occur in each of the following genes: LQT-1: KCNQ1; LQT-2: KCNH2 gene; LQT-3: SCN5A; LQT-4: ANK2 gene; LQT-5: KCNE1 gene; LQT-6: KCNE2 gene; LQT-7: KCNJ2 gene; LQT-8: CACNA1C gene; LQT-9: CAV3 gene; LQT-10: SCN4B gene; LQT-11: AKAP9 gene; LQT-12 gene SNTA1; LQT-13: KCNJ5 gene.
The long QT syndrome type 1, associated with mutations in the KCNQ1 (Potassium inwardly-rectifying cannel, subfamily J, member 2) gene, located on the short arm of chromosome 11 (11p15.5). KCNQ1 channels with protein are active in the inner ear and the heart muscle, which carry potassium ions outside the cell. In the inner ear helps maintain proper ions required for normal hearing. In the heart, the channels involved in recharging the heart muscle after each heartbeat to keep a regular rhythm. KCNQ1 protein is also produced in the kidney, lung, stomach and intestine where it is responsible for transporting molecules across the cell membrane. KCNQ1 protein interacts with the KCNE family proteins (such as KCNE1 protein) to form functional potassium channels. Four alpha subunits, each encoded by KCNQ1, form the structure of each channel. A beta subunit, encoded by the gene family KCNE, joins the channel to regulate its activity. It is thought that the molecule called PIP2 must bind to proteins consisting of KCNQ1 to function normally channels. PIP2 active ion channel and helps stabilize when open, which allows the flow of ions outside the cell. Disruption of these channel proteins KCNQ1 found in: long QT type 1 family atrial fibrillation, Jervell and Lange-Nielsen, Romano-Ward syndrome, Short QT syndrome and sudden death syndrome syndrome childhood (SIDS).
QT syndrome type 2 long, associated with mutations in the KCNH2 gene (voltage-gated potassium cannel subfamily H, member 2), located on the long arm of chromosome 7 (7q36.1). This gene belongs to the family of genes called KCN (potassium channels) encoding proteins forming potassium channels in the cell membrane. These channels carry positively charged ions like potassium, inside and outside the cell, very important to generate and transmit electrical signals. In cardiac muscle, these ion channels play a critical role in maintaining normal heart rhythm. Mutations in them increase the activity of the channels, which modifies the flow of potassium ions into cells, leading to impaired cardiac contractility, causing abnormal heart rhythm characteristic of short QT syndrome and syndrome long QT type 2. the specific role of potassium channel dependent on its protein components, and his physical location. The channels in which the protein participates KNCH2 are active in cardiac muscle, which transport ions outside the cell. This form of ion transport is involved in reloading of the heart muscle after each contraction to maintain a steady pace. The KCNH2 protein is also present on nerve cells and some immune cells such as microglia in the central nervous system. This protein interacts with the KCNE2 protein to form the functional potassium channel. Four alpha subunits, encoded by the KCNH2 gene, form the channel structure. A beta subunit, encoded by the KCNE2 gene, binds to the channel and regulates its activity. By increasing the flow of potassium out of heart cells at a critical time during the heartbeat, this mutation is responsible for changes in heart rate own long QT type 2 KCNH2 gene mutations syndrome, also found in the Romano-Ward syndrome.
The long QT syndrome type 3, associated with mutations in the SCN5A gene, located on the short arm of chromosome 3 (3p21). This gene belongs to a family of genes SCN (Sodium cannel, voltage-gated, type V, alpha subunit) that encode proteins intended to form sodium channels. These channels convey sodium positively charged ions into cardiac muscle cells and have a primary role in the ability of cells to generate and transmit electrical signals, regulating heart normal rhythm. Sodium channel of cardiac muscle open and close to control the flow of ions into cardiac muscle cells. By changing the electrical properties of these cells, the sodium channels have a central role for the initiation of the heartbeat, coordinating atrial and ventricular contractions, and maintaining normal heart rhythm. Mutations in the SCN5A gene, alter the structure or function of these channels, which reduces the flow of ions into cells, and consequently the frequency of the heartbeat, causing an abnormal rhythm characteristic of the syndrome.
The long QT syndrome type 4, is linked to mutations in the gene ANK2 (ankyrin 2, neuronal), located on the long arm of chromosome 4 (4q25-q27). This gene encodes the "ankyrin 2" protein, which belongs to the family of "Ankirinas" that interacts with many other proteins in body cells. The ankirinas make some proteins are inserted in their proper location in the cell membrane and are anchored to the cytoskeleton, and is involved in important cellular functions including movement, growth and cell division. Ankyrin-2 protein is active in many cell types, mainly in the brain and heart. This protein is directed to the ion channels. In the heart, the flow of ions (sodium, potassium, calcium), through the channels is critical for the heartbeat occurs and normal rhythm is maintained. Ankyrin-2 inserts these channels in its proper location in the membrane, so that it can regulate the flow of ions inside and outside of the cardiac muscle cell.
The long QT syndrome type 5, is due to mutations in KCNE1 gene (voltage-gated potassium cannel, sK-related family, member 1), located on the long arm of chromosome 21 (21q22.12). This gene belongs to the family of KCN genes (potassium channels) and encodes a protein that regulates the activity of potassium channels, which transport potassium ions into and out of the cell and play a key role in the ability of cells to generate and transmit electrical signals. The role of potassium channels depends on their protein components and their bodily location. The KCNE1 protein, regulates the channel formed by four alpha subunits encoded by KCNQ1, which form the channel structure. A beta subunit, encoded by KCNE1 gene binds to and regulates channel activity. These channels are involved in the inner ear and the heart muscle, which transport ions into and out of cells. In cardiac muscle channels muscle recharged after each contraction to maintain the heartbeat.
The long QT syndrome type 6, related to mutations in the KCNE2 gene (voltage-gated potassium cannel, sK-related famuily, member 2), located on the long arm of chromosome 21 (21q22.12), encoding the protein regulating the activity of potassium channels. These channels carry potassium ions into and out of the cell, and therefore play a major role in the ability of the cell to generate and transport electrical signals. The KCNE2 protein regulates several ion channels, including a channel formed by the KCNH2 gene encoded that are present in the heart muscle where potassium ions transported to outside cells proteins. The KCNH2 and KCNE2 proteins interact to form a functional channel. Four alpha subunits encoded by the KCNH2 gene form the channel structure and a beta subunit KCNE2 binds to regulate activity.
The long QT syndrome type 7, associated with mutations in the gene KCNJ2 (voltage-gated potassium cannel, KQT-like subfamily, member 1), located on the long arm of chromosome 17 (17q24.3). Ion channels in which the protein participates KCNJ2 are present in skeletal and cardiac muscle cells, which transport ions into the cell. In skeletal muscle, these channels are involved in muscle contraction and relaxation, which enables movement. In the heart, the channels can charge cardiac muscle following each beat to maintain normal rhythm. In the formation of these channels plus the KCNJ2 protein, it is also necessary that the protein is PIP2 set. This protein activates the ion channel and helps stabilize in an open state, whereby ions flow through the membrane. Mutations in this gene are also responsible Andersen-Tawil syndrome and family atrial fibrillation.
The long QT syndrome type 8 relates to gene mutations CACNA1C (calcium cannel, voltage dependent, L type, alpha 1C subunit), located on the short arm of chromosome 12 (12p13.33). This gene encodes the "alpha-1C subunit of L-type voltage-dependent calcium cannel" protein (alpha 1C subunit L - channel voltage - dependent calcium). The gene encoding calcium channel carrying calcium ions into the cell and play a key role to generate and transmit electrical signals, plus intercellular communication, muscle contraction and regulation of certain genes. CACNA1C coded channels are called CaV1.2, and are in the heart and brain. In the heart open and close to control the flow of calcium ions into cardiac muscle cells.
The long QT syndrome type 9 is due to mutations in the gene CAV3 (caveolin 3), located on the short arm of chromosome 3 (3p25). This gene encodes the protein caveolin-3, which is in the membrane of muscle cells, where it is the main component of "caveolae" sipes membranes as muscle cells. In these structures caveolin-3 organizes other molecules important for signals and maintaining cell structure.
The long QT syndrome type 10, associated with mutations in the gene SCN4B (sodium cannel, voltage gated, type IV, beta subunit), located in the arm on the long arm of chromosome 11 (11q23.3). This gene encodes a protein that form the beta subunits of sodium channels. These subunits interact with the alpha subunits to change the kinetics of the sodium channel.
The long QT syndrome type 11, associated with mutations in the AKAP9 (A kinase anchor protein 9) gene, located on the arm on the long arm of chromosome 7 (7q21-22) and encodes proteins "A kinase anchor proteins" , which they are a diverse group of proteins that share the function of binding to the regulatory subunit of protein kinase a (PKA) protein, and confine the enzyme specific locations of the cell. Encoding AKAP protein family ( "A Kinase Anchor Proteins). The gene encodes two isofomas of the protein located in the centrosome and the Golgi and interact with several proteins signals multiway signal transduction (protein kinase A type II serine / threonine kinase N, phosphatase 1, phosphatase 2 to, kinase C-epsilon, phosphodiesterase 4D3).
The long QT syndrome type 12, associated with mutations in the gene SNTA1 (syntrophin, alpha 1), located on the long arm of chromosome 20 (20q11.2). This gene encodes the synthrophins cytoplasmic proteins that are peripheral components of complex syntrophin associated proteins. The N-terminal domain of this syntrophin interacts with the C-terminus of the alpha subunit of forming pores (SCN5A) sodium channel complex oxide synthase Nitric PMCA4b cardiomyocytes.
The long QT syndrome type 13, associated with mutations in the KCNJ5 gene (potassium inwardly-rectifying cannel, subfamily J, member 5), located on the long arm of chromosome 11 (11q24), encoding the integral membrane protein that regulates the potassium channel, allowing flow inside potassium controlled by G protein can be associated with protein G of potassium channels to form a heteromultimeric complex pores.
Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with long QT syndrome by complete PCR amplification of the exons of KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CPVT1, CAV3, KCNJ5 genes , CACNA1C and SCN4B, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).