Familial hypertrophic cardiomyopathy (Familial hypertrophic cardiomyopathy) - MYH7, MYBPC3, TNNT2 and TNNI3
Familial hypertrophic cardiomyopathy is a process characterized by left ventricular hypertrophy in the absence of cardiac haemodynamic factors or which could be justified as aortic stenosis or lasting hypertension. This process is a primary disease of cardiac myocytes, characterized by cardiac hypertrophy concentric with asymmetric frequency with a dilated left ventricle with more frequent ventricular septal involvement, and with preserved systolic function or increased.
In most cases the process is asymptomatic or mildly symptomatic. When symptomatic, the most common manifestations are dyspnea and chest pain. Dyspnea is motivated by the high diastolic pressure in the left ventricle diastolic dysfunction following, especially with exercise. Chest pain is motivated by myocardial hypoperfusion and increased oxygen demand. Other symptoms and signs include palpitations, dizziness, syncope or presyncope, atrial fibrillation, supraventricular arrhythmias, sudden cardiac arrest and sudden death. Clinical differences may vary from one individual to another, and even between individuals of the same family in which there are several affected. Most cases are manifested clinically in adolescence or young adulthood, but can also manifest belatedly in old age or early stage in childhood.
Most cases of familial hypertrophic cardiomyopathy are due to mutations in the MYH7 (myosin, heavy chain 7, muscle cardiac, beta), MYBPC3 (myosin binding protein C, cardiac), TNNT2 (Troponin T2, cardiac type) or TNNI3 gene (I3 troponin, cardiac type). Other genes (ACTC1, ACTN2, CALR3, CSRP3, JPH2, MYL2, MYL3, MYOZ2, NEXN, PLN, PRKAG2, TCAP, TPM1, TTN and VCL), and still others that have not been identified, may also be involved in the development of the illness.
MYH7 (myosin, heavy chain 7, cardiac muscle, beta) gene, located on the long arm of chromosome 14 (14q12), encodes a protein known as cardiac ?-myosin heavy chain. This protein is found in the heart muscle and skeletal muscle fibers of type I cells cardiac and skeletal muscle, the form of ?-myosin heavy chain part of a larger protein called myosin type II. Each protein myosin type II consists of two heavy chains (encoded from MYH7) and two pairs of regulatory light chain (encoded from other genes). Heavy chains have two parts: a head region and tail region. The head region, called the motor domain interacts with a protein called actin thin filament. The region long tail interacts with other proteins, including the regions of other tail proteins myosin. Type II myosin generates mechanical force needed for muscles to contract and is an integral part of the sarcomeres. Mutations in MYH7 are responsible for up to 35% of cases of familial hypertrophic cardiomyopathy. Most MYH7 genetic mutations associated with the disease consist of amino acid changes in the ?-myosin heavy chain protein. Although it is likely that the altered protein is incorporated into the thick filament, it can not function properly. It is unclear how genetic mutations in MYH7 result the characteristics of familial hypertrophic cardiomyopathy.
MYBPC3 (myosin binding protein C, cardiac) gene, located on the short arm of chromosome 11 (11p11.2), encoding cardiac myosin binding protein C (cardiac MyBP-C), located in the cells of heart muscle. In these cells, MyBP-C is associated with the sarcomeres. Sarcomere consist of thick and thin filaments. The thick and thin filaments adhere to each other, allowing the filaments to move relative to each other so that muscles to contract. In cardiac muscle sarcomeres MyBP-C binds to the thick filaments and prevents decomposes. MyBP-C also regulates the rate of muscle contraction. Mutations in MYBPC3 are responsible for up to 30% of cases of familial hypertrophic cardiomyopathy. Although these genetic changes result in an abnormally short MyBP-C or altered function protein, it is unclear how these changes cause hypertrophy of the heart muscle.
TNNT2 (Troponin T2, cardiac type) gene, located on the long arm of chromosome 1 (1q32), encodes a protein called cardiac troponin T, which is found exclusively in cardiac muscle. This protein is one of the three proteins which comprise the troponin complex protein in cardiac muscle cells. The troponin complex is part of the sarcomere. This complex, along with calcium, helps regulate heart muscle contraction. Mutations in the gene have been identified TNNT2 in approximately 5% of cases of familial hypertrophic cardiomyopathy. Most mutations TNNT2 associated with disease consist of amino acid changes in cardiac troponin T. Although protein is likely that the altered protein is incorporated in the troponin complex, it may not function properly. An anomaly or deficiency of troponin T can impair the function of the sarcomere, disrupting normal heart muscle contraction. However, it is unclear how mutations result TNNT2 characteristics of familial hypertrophic cardiomyopathy.
The TNNI3 (I3 troponin, cardiac type) gene, located on the long arm of chromosome 19 (19q13.4), encodes troponin I, which is found exclusively in the heart. as troponin T, encoded from TNNT2. This protein is one of the three proteins which comprise the troponin complex protein in cardiac muscle cells. Troponin I helps coordinate cardiac contraction. When calcium levels are low, the troponin complex binds to the thin filament. This blocks the binding interaction between the thick and thin filaments needed for muscle contraction. An increase in calcium levels causes structural changes in another protein called troponin C complex, which subsequently activates the troponin complex to detach the thin filament, allowing the heart muscle to contract. Mutations in the gene have been identified TNNI3 less than 5% of cases of familial hypertrophic cardiomyopathy. These mutations consist of amino acid changes in the protein troponin I, which leads to the synthesis of an altered protein, although likely to be incorporated in the troponin complex may not operate properly. An abnormality or deficiency of troponin I can impair the function of the sarcomere, disrupting normal heart muscle contraction.
Hypertrophic cardiomyopathy family is inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. Rarely, the two copies of the gene are altered, leading to signs and more severe symptoms. In most cases, an affected person has a parent with the disease.
Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with familial hypertrophic cardiomyopathy, by complete PCR amplification of exons MYH7, MYBPC3, TNNT2 and TNNI3, or other genes that have been implicated genes, 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).