Altre denominazioni; simboli

• ESSENTIAL LIGHT CHAIN OF MYOSIN
• ELC OF MYOSIN
• MYOSIN, LIGHT CHAIN 1, SLOW, B; MLC1SB
• MYOSIN, LIGHT CHAIN 1, VENTRICULAR; MLC1V

Testo

The myosin molecule consists di 2 heavy chains e 4 associata light chains. Due of the light chains are regulatory light chains (RLC) codificati by the MYL2 gene (160781), e 2 are alkali light chains, o essential light chains (ELC), codificati by the MYL3 gene. The light chains stabilize the long alpha-helical collo of the myosin head. Distinct isoforms of the myosin alkali light chains are presenti in differenti tessuti. Their function in striated muscle è solo partially understood.

Cloning

Hoffmann ed altri (1988) presentarono the complete nucleotide sequenza of human ventricular myosin light chain-1.

Gene Structure

Fodor ed altri (1989) trovarono che the MYL3 gene has 7 exons, the last of which è completely untranslated 3-prime sequenza.

Mappatura

Darras ed altri (1987) e Fodor ed altri (1989) used a fragment from the 3-prime end of the human myosin alkali light chain gene, isolated by screening a partial genomic library con rat skeletal myosin light chain cDNA, in studies of somatic cell hybrids. The gene venne trovata to map to 3p. In the mouse, the Myl3 gene on distal chromosome 9 codes the ventricular e slow muscoli scheletrici isoforms. Altre loci in che area, such come Bgl e Acy, are homologous to geni on human chromosome 3p. It è possible che the gene mapped by Darras ed altri (1987) è the human homolog of mouse Myl3; thus the designation MYL3 è used per the human locus.

Using a panel of man-rodent somatic cell hybrids, Cohen-Haguenauer ed altri (1989) mapped the MYL3 gene to chromosome 3. This finding era in keeping con the assignment of the corresponding gene to mouse chromosome 9.

Funzione genica

Laugwitz ed altri (2001) mostrava che caspase-3 (600636) activation directly influences contractile performance of failing ventricular myocytes, e can be corrected via adenovirus-mediated gene delivery of the potent caspase inhibitor p35 con a positive impact on contractility. To determine the molecular mechanism by which activated caspase-3 causes a deterioramento of cardiac function, Moretti ed altri (2002) used a modified yeast 2-hybrid sistema to screen per caspase-3 interacting proteins of the cardiac cytoskeleton. They identificarono ventricular essential myosin light chain (MYL3), symbolized vMLC1 by gli autori, come a target of caspase-3. They demonstrated che MYL3 cleavage in failing miocardio in vivo era associata con a morphologic disruption of the organized MYL3 staining of sarcomeres, e con a riduzione in myocyte contractile performance. Adenoviral gene transfer of p35 in vivo prevented caspase-3 activation e MYL3 cleavage, con positive impact on contractility. These data suggerivano che direct cleavage of the myosin light chain by activated caspase-3 may contribute to depression of myocyte function by altering crossbridge interaction fra myosin e actin molecole. Therefore, activation of apoptotic pathways in the heart may lead to contractile disfunzione before cell death.

Genetica molecolare

Poetter ed altri (1996) analyzed the MYL3 gene in 383 non imparentati probands con hypertrophic cardiomiopatia (see CMH8, 608751) e identificarono a heterozygous missense mutazione a a conserved residue (M149V; 160790.0001) che segregated con malattia in a large 3-generazioni famiglia. Linkage analisi of la mutazione against hypertrophy gave a lod score of 6.2 con no recombinants. Six of 13 membri della famiglia affetti avevano unusual mid-left ventricular chamber thickening on echocardiography. Poetter ed altri (1996) screened the MYL3 gene in 16 aggiuntivi CMH pazienti con simile mid-left ventricular chamber thickening e identificarono a differenti heterozygous missense mutazione (R154H; 160790.0002) in a young boy con massive chamber obstruction. Neither these nor any altra mutazioni in MYL3 erano trovarono in 378 control chromosomes o 762 chromosomes from non imparentati CMH kindreds. Poetter ed altri (1996) also analyzed the MYL2 gene (160761) in CMH pazienti e identificarono 3 differenti heterozygous mutazioni in 5 individui affetti, 4 of whom avevano 'strikingly simile' mid-left ventricular chamber hypertrophy (see CMH10, 608758).

In 3 sibs of a consanguineous famiglia con insorgenza precoce hypertrophic cardiomiopatia caratterizzata by midcavitary hypertrophy e restrictive physiology, Olson ed altri (2002) condussero haplotype analisi using polymorphic DNA markers spanning geni known to cause hypertrophic cardiomiopatia. The results suggerivano che, in keeping con the consanguineous famiglia history, il fenotipo might be an autosomica recessive form of CMH causata da mutazione in MYL3. A homozygous MYL3 mutazione, glu143 to lys (E143K; 160790.0003), era successivamente identificarono in i probandi. Gli autori suggerivano che, in contrast to autosomica dominante CMH mutazioni nel quale functional studies demonstrate a dominant-negative effect, E143K era probabilmente to cause loss of function. In support di questo hypothesis, gli autori trovarono che heterozygotes erano non affetti on the basis of electrocardiography e echocardiography. In addition, this mutazione affetti an amino acid in a surface-exposed loop of the essential light chain e era unlikely to disrupt protein conformation o stability. Site-directed mutagenesis of the corresponding loop domain (Ho e Chisholm, 1997) avevano no effect on binding fra myosin heavy e light chains, ma significativamente ridotta actin-activated ATPase attività e in vitro motility. Thus, Olson ed altri (2002) conclusero che questa famiglia demonstrated a true autosomica recessive form of CMH8, caratterizzata by a unico pattern of hypertrophy previously descrivono in autosomica dominante CMH8.

In i probandi from a CMH famiglia previously descrivono by Maron ed altri (1982), nel quale 6 of 12 affetti membri avevano typical asimmetrica hypertrophy e 6 avevano ventricular septal hypertrophy che era localized to the apical region of the left ventricle, Arad ed altri (2005) identificarono heterozygosity per the M149V mutazione. Arad ed altri (2005) noted che perché the classification of hypertrophy come midcavitary o apical might in part reflect the evolution of diagnostic imaging techniques from angiography, by which midcavitary hypertrophy era historically recognized, to echocardiography e MRI, these may represent overlapping morphologies.

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Special Report

• Varianti alleliche (Dettagli)
• Gene map