Full text data of MYL3
MYL3
[Confidence: low (only semi-automatic identification from reviews)]
Myosin light chain 3 (Cardiac myosin light chain 1; CMLC1; Myosin light chain 1, slow-twitch muscle B/ventricular isoform; MLC1SB; Ventricular/slow twitch myosin alkali light chain)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Myosin light chain 3 (Cardiac myosin light chain 1; CMLC1; Myosin light chain 1, slow-twitch muscle B/ventricular isoform; MLC1SB; Ventricular/slow twitch myosin alkali light chain)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P08590
ID MYL3_HUMAN Reviewed; 195 AA.
AC P08590; B2R534; Q9NRS8;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Myosin light chain 3;
DE AltName: Full=Cardiac myosin light chain 1;
DE Short=CMLC1;
DE AltName: Full=Myosin light chain 1, slow-twitch muscle B/ventricular isoform;
DE Short=MLC1SB;
DE AltName: Full=Ventricular/slow twitch myosin alkali light chain;
GN Name=MYL3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3417683;
RA Kurabayashi M., Komuro I., Tsuchimochi H., Takaku F., Yazaki Y.;
RT "Molecular cloning and characterization of human atrial and
RT ventricular myosin alkali light chain cDNA clones.";
RL J. Biol. Chem. 263:13930-13936(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3357795; DOI=10.1093/nar/16.5.2353;
RA Hoffmann E., Shi Q.W., Floroff M., Mickle D.A.G., Wu T.-W.,
RA Olley P.M., Jackowski G.;
RT "Molecular cloning and complete nucleotide sequence of a human
RT ventricular myosin light chain 1.";
RL Nucleic Acids Res. 16:2353-2353(1988).
RN [3]
RP SEQUENCE REVISION.
RA Jackowski G.;
RL Submitted (MAY-1988) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2789520;
RA Fodor W.L., Darras B., Seharaseyon J., Falkenthal S., Francke U.,
RA Vanin E.F.;
RT "Human ventricular/slow twitch myosin alkali light chain gene
RT characterization, sequence, and chromosomal location.";
RL J. Biol. Chem. 264:2143-2149(1989).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Huang R., Peng B., Zhou G., Gong Z.;
RT "The sequence of human cardiac myosin light chain I (CMLC-1) from a
RT Chinese patient and the preparation of monoclonal antibody to
RT CHCMLC1.";
RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP PROTEIN SEQUENCE OF 20-27; 34-40; 95-100; 124-129; 139-142 AND
RP 155-171.
RC TISSUE=Heart;
RX PubMed=7498159; DOI=10.1002/elps.11501601192;
RA Kovalyov L.I., Shishkin S.S., Efimochkin A.S., Kovalyova M.A.,
RA Ershova E.S., Egorov T.A., Musalyamov A.K.;
RT "The major protein expression profile and two-dimensional protein
RT database of human heart.";
RL Electrophoresis 16:1160-1169(1995).
RN [10]
RP METHYLATION AT ALA-2.
RX PubMed=3979397; DOI=10.1111/j.1432-1033.1985.tb08809.x;
RA Henry G.D., Trayer I.P., Brewer S., Levine B.A.;
RT "The widespread distribution of alpha-N-trimethylalanine as the N-
RT terminal amino acid of light chains from vertebrate striated muscle
RT myosins.";
RL Eur. J. Biochem. 148:75-82(1985).
RN [11]
RP VARIANTS CMH8 VAL-149 AND HIS-154.
RX PubMed=8673105; DOI=10.1038/ng0596-63;
RA Poetter K., Jiang H., Hassanzadeh S., Master S.R., Chang A.,
RA Dalakas M.C., Rayment I., Sellers J.R., Fananapazir L., Epstein N.D.;
RT "Mutations in either the essential or regulatory light chains of
RT myosin are associated with a rare myopathy in human heart and skeletal
RT muscle.";
RL Nat. Genet. 13:63-69(1996).
RN [12]
RP VARIANT CMH8 LYS-143.
RX PubMed=12021217; DOI=10.1161/01.CIR.0000018444.47798.94;
RA Olson T.M., Karst M.L., Whitby F.G., Driscoll D.J.;
RT "Myosin light chain mutation causes autosomal recessive cardiomyopathy
RT with mid-cavitary hypertrophy and restrictive physiology.";
RL Circulation 105:2337-2340(2002).
RN [13]
RP VARIANT CMH8 GLY-56.
RX PubMed=12707239; DOI=10.1161/01.CIR.0000066323.15244.54;
RA Richard P., Charron P., Carrier L., Ledeuil C., Cheav T.,
RA Pichereau C., Benaiche A., Isnard R., Dubourg O., Burban M.,
RA Gueffet J.-P., Millaire A., Desnos M., Schwartz K., Hainque B.,
RA Komajda M.;
RT "Hypertrophic cardiomyopathy: distribution of disease genes, spectrum
RT of mutations, and implications for a molecular diagnosis strategy.";
RL Circulation 107:2227-2232(2003).
RN [14]
RP ERRATUM.
RA Richard P., Charron P., Carrier L., Ledeuil C., Cheav T.,
RA Pichereau C., Benaiche A., Isnard R., Dubourg O., Burban M.,
RA Gueffet J.-P., Millaire A., Desnos M., Schwartz K., Hainque B.,
RA Komajda M.;
RL Circulation 109:3258-3258(2004).
CC -!- FUNCTION: Regulatory light chain of myosin. Does not bind calcium.
CC -!- SUBUNIT: Myosin is a hexamer of 2 heavy chains and 4 light chains.
CC -!- PTM: The N-terminus is blocked.
CC -!- PTM: N-terminus is methylated by METTL11A/NTM1 (By similarity).
CC -!- DISEASE: Cardiomyopathy, familial hypertrophic 8 (CMH8)
CC [MIM:608751]: A hereditary heart disorder characterized by
CC ventricular hypertrophy, which is usually asymmetric and often
CC involves the interventricular septum. The symptoms include
CC dyspnea, syncope, collapse, palpitations, and chest pain. They can
CC be readily provoked by exercise. The disorder has inter- and
CC intrafamilial variability ranging from benign to malignant forms
CC with high risk of cardiac failure and sudden cardiac death.
CC Rarely, patients present a variant of familial hypertrophic
CC cardiomyopathy, characterized by mid-left ventricular chamber
CC thickening. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Contains 3 EF-hand domains.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MYL3";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M24122; AAA59895.1; -; mRNA.
DR EMBL; X07373; CAA30292.1; -; mRNA.
DR EMBL; M24247; AAA59851.1; -; Genomic_DNA.
DR EMBL; M24242; AAA59851.1; JOINED; Genomic_DNA.
DR EMBL; M24243; AAA59851.1; JOINED; Genomic_DNA.
DR EMBL; M24244; AAA59851.1; JOINED; Genomic_DNA.
DR EMBL; M24245; AAA59851.1; JOINED; Genomic_DNA.
DR EMBL; M24246; AAA59851.1; JOINED; Genomic_DNA.
DR EMBL; AF174483; AAF91089.1; -; mRNA.
DR EMBL; AK312044; BAG34981.1; -; mRNA.
DR EMBL; CH471055; EAW64791.1; -; Genomic_DNA.
DR EMBL; BC009790; AAH09790.1; -; mRNA.
DR PIR; B30881; MOHU3V.
DR RefSeq; NP_000249.1; NM_000258.2.
DR UniGene; Hs.517939; -.
DR ProteinModelPortal; P08590; -.
DR SMR; P08590; 49-194.
DR IntAct; P08590; 4.
DR STRING; 9606.ENSP00000292327; -.
DR PhosphoSite; P08590; -.
DR DMDM; 127149; -.
DR UCD-2DPAGE; P08590; -.
DR PaxDb; P08590; -.
DR PRIDE; P08590; -.
DR DNASU; 4634; -.
DR Ensembl; ENST00000292327; ENSP00000292327; ENSG00000160808.
DR Ensembl; ENST00000395869; ENSP00000379210; ENSG00000160808.
DR GeneID; 4634; -.
DR KEGG; hsa:4634; -.
DR UCSC; uc003cql.1; human.
DR CTD; 4634; -.
DR GeneCards; GC03M046899; -.
DR HGNC; HGNC:7584; MYL3.
DR HPA; CAB018662; -.
DR HPA; HPA016564; -.
DR MIM; 160790; gene.
DR MIM; 608751; phenotype.
DR neXtProt; NX_P08590; -.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR PharmGKB; PA31381; -.
DR eggNOG; COG5126; -.
DR HOGENOM; HOG000233018; -.
DR HOVERGEN; HBG012180; -.
DR InParanoid; P08590; -.
DR KO; K12749; -.
DR OMA; RPKEAEF; -.
DR OrthoDB; EOG7HQN9N; -.
DR Reactome; REACT_17044; Muscle contraction.
DR ChiTaRS; MYL3; human.
DR GeneWiki; MYL3; -.
DR GenomeRNAi; 4634; -.
DR NextBio; 17840; -.
DR PMAP-CutDB; P08590; -.
DR PRO; PR:P08590; -.
DR ArrayExpress; P08590; -.
DR Bgee; P08590; -.
DR CleanEx; HS_MYL3; -.
DR Genevestigator; P08590; -.
DR GO; GO:0031672; C:A band; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031674; C:I band; IDA:BHF-UCL.
DR GO; GO:0005859; C:muscle myosin complex; TAS:ProtInc.
DR GO; GO:0003785; F:actin monomer binding; IDA:BHF-UCL.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0003774; F:motor activity; IEA:Ensembl.
DR GO; GO:0032038; F:myosin II heavy chain binding; NAS:BHF-UCL.
DR GO; GO:0008307; F:structural constituent of muscle; TAS:ProtInc.
DR GO; GO:0060048; P:cardiac muscle contraction; IMP:BHF-UCL.
DR GO; GO:0030049; P:muscle filament sliding; TAS:Reactome.
DR GO; GO:0032781; P:positive regulation of ATPase activity; ISS:BHF-UCL.
DR GO; GO:0006942; P:regulation of striated muscle contraction; IMP:BHF-UCL.
DR GO; GO:0002026; P:regulation of the force of heart contraction; IMP:BHF-UCL.
DR GO; GO:0007519; P:skeletal muscle tissue development; IEA:Ensembl.
DR GO; GO:0055010; P:ventricular cardiac muscle tissue morphogenesis; IMP:BHF-UCL.
DR Gene3D; 1.10.238.10; -; 2.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR002048; EF_hand_dom.
DR PROSITE; PS50222; EF_HAND_2; 3.
PE 1: Evidence at protein level;
KW Cardiomyopathy; Complete proteome; Direct protein sequencing;
KW Disease mutation; Methylation; Motor protein; Muscle protein; Myosin;
KW Reference proteome; Repeat.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 195 Myosin light chain 3.
FT /FTId=PRO_0000198696.
FT DOMAIN 49 86 EF-hand 1.
FT DOMAIN 128 163 EF-hand 2.
FT DOMAIN 163 195 EF-hand 3.
FT MOD_RES 2 2 N,N,N-trimethylalanine (Probable).
FT VARIANT 56 56 E -> G (in CMH8).
FT /FTId=VAR_019842.
FT VARIANT 143 143 E -> K (in CMH8; autosomal recessive).
FT /FTId=VAR_019843.
FT VARIANT 149 149 M -> V (in CMH8; with mid-left
FT ventricular chamber thickening).
FT /FTId=VAR_004599.
FT VARIANT 154 154 R -> H (in CMH8; with mid-left
FT ventricular chamber thickening).
FT /FTId=VAR_004600.
FT CONFLICT 171 171 K -> R (in Ref. 5; AAF91089).
SQ SEQUENCE 195 AA; 21932 MW; 306CF328841729DD CRC64;
MAPKKPEPKK DDAKAAPKAA PAPAPPPEPE RPKEVEFDAS KIKIEFTPEQ IEEFKEAFML
FDRTPKCEMK ITYGQCGDVL RALGQNPTQA EVLRVLGKPR QEELNTKMMD FETFLPMLQH
ISKNKDTGTY EDFVEGLRVF DKEGNGTVMG AELRHVLATL GERLTEDEVE KLMAGQEDSN
GCINYEAFVK HIMSS
//
ID MYL3_HUMAN Reviewed; 195 AA.
AC P08590; B2R534; Q9NRS8;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Myosin light chain 3;
DE AltName: Full=Cardiac myosin light chain 1;
DE Short=CMLC1;
DE AltName: Full=Myosin light chain 1, slow-twitch muscle B/ventricular isoform;
DE Short=MLC1SB;
DE AltName: Full=Ventricular/slow twitch myosin alkali light chain;
GN Name=MYL3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3417683;
RA Kurabayashi M., Komuro I., Tsuchimochi H., Takaku F., Yazaki Y.;
RT "Molecular cloning and characterization of human atrial and
RT ventricular myosin alkali light chain cDNA clones.";
RL J. Biol. Chem. 263:13930-13936(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3357795; DOI=10.1093/nar/16.5.2353;
RA Hoffmann E., Shi Q.W., Floroff M., Mickle D.A.G., Wu T.-W.,
RA Olley P.M., Jackowski G.;
RT "Molecular cloning and complete nucleotide sequence of a human
RT ventricular myosin light chain 1.";
RL Nucleic Acids Res. 16:2353-2353(1988).
RN [3]
RP SEQUENCE REVISION.
RA Jackowski G.;
RL Submitted (MAY-1988) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2789520;
RA Fodor W.L., Darras B., Seharaseyon J., Falkenthal S., Francke U.,
RA Vanin E.F.;
RT "Human ventricular/slow twitch myosin alkali light chain gene
RT characterization, sequence, and chromosomal location.";
RL J. Biol. Chem. 264:2143-2149(1989).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Huang R., Peng B., Zhou G., Gong Z.;
RT "The sequence of human cardiac myosin light chain I (CMLC-1) from a
RT Chinese patient and the preparation of monoclonal antibody to
RT CHCMLC1.";
RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP PROTEIN SEQUENCE OF 20-27; 34-40; 95-100; 124-129; 139-142 AND
RP 155-171.
RC TISSUE=Heart;
RX PubMed=7498159; DOI=10.1002/elps.11501601192;
RA Kovalyov L.I., Shishkin S.S., Efimochkin A.S., Kovalyova M.A.,
RA Ershova E.S., Egorov T.A., Musalyamov A.K.;
RT "The major protein expression profile and two-dimensional protein
RT database of human heart.";
RL Electrophoresis 16:1160-1169(1995).
RN [10]
RP METHYLATION AT ALA-2.
RX PubMed=3979397; DOI=10.1111/j.1432-1033.1985.tb08809.x;
RA Henry G.D., Trayer I.P., Brewer S., Levine B.A.;
RT "The widespread distribution of alpha-N-trimethylalanine as the N-
RT terminal amino acid of light chains from vertebrate striated muscle
RT myosins.";
RL Eur. J. Biochem. 148:75-82(1985).
RN [11]
RP VARIANTS CMH8 VAL-149 AND HIS-154.
RX PubMed=8673105; DOI=10.1038/ng0596-63;
RA Poetter K., Jiang H., Hassanzadeh S., Master S.R., Chang A.,
RA Dalakas M.C., Rayment I., Sellers J.R., Fananapazir L., Epstein N.D.;
RT "Mutations in either the essential or regulatory light chains of
RT myosin are associated with a rare myopathy in human heart and skeletal
RT muscle.";
RL Nat. Genet. 13:63-69(1996).
RN [12]
RP VARIANT CMH8 LYS-143.
RX PubMed=12021217; DOI=10.1161/01.CIR.0000018444.47798.94;
RA Olson T.M., Karst M.L., Whitby F.G., Driscoll D.J.;
RT "Myosin light chain mutation causes autosomal recessive cardiomyopathy
RT with mid-cavitary hypertrophy and restrictive physiology.";
RL Circulation 105:2337-2340(2002).
RN [13]
RP VARIANT CMH8 GLY-56.
RX PubMed=12707239; DOI=10.1161/01.CIR.0000066323.15244.54;
RA Richard P., Charron P., Carrier L., Ledeuil C., Cheav T.,
RA Pichereau C., Benaiche A., Isnard R., Dubourg O., Burban M.,
RA Gueffet J.-P., Millaire A., Desnos M., Schwartz K., Hainque B.,
RA Komajda M.;
RT "Hypertrophic cardiomyopathy: distribution of disease genes, spectrum
RT of mutations, and implications for a molecular diagnosis strategy.";
RL Circulation 107:2227-2232(2003).
RN [14]
RP ERRATUM.
RA Richard P., Charron P., Carrier L., Ledeuil C., Cheav T.,
RA Pichereau C., Benaiche A., Isnard R., Dubourg O., Burban M.,
RA Gueffet J.-P., Millaire A., Desnos M., Schwartz K., Hainque B.,
RA Komajda M.;
RL Circulation 109:3258-3258(2004).
CC -!- FUNCTION: Regulatory light chain of myosin. Does not bind calcium.
CC -!- SUBUNIT: Myosin is a hexamer of 2 heavy chains and 4 light chains.
CC -!- PTM: The N-terminus is blocked.
CC -!- PTM: N-terminus is methylated by METTL11A/NTM1 (By similarity).
CC -!- DISEASE: Cardiomyopathy, familial hypertrophic 8 (CMH8)
CC [MIM:608751]: A hereditary heart disorder characterized by
CC ventricular hypertrophy, which is usually asymmetric and often
CC involves the interventricular septum. The symptoms include
CC dyspnea, syncope, collapse, palpitations, and chest pain. They can
CC be readily provoked by exercise. The disorder has inter- and
CC intrafamilial variability ranging from benign to malignant forms
CC with high risk of cardiac failure and sudden cardiac death.
CC Rarely, patients present a variant of familial hypertrophic
CC cardiomyopathy, characterized by mid-left ventricular chamber
CC thickening. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Contains 3 EF-hand domains.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MYL3";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M24122; AAA59895.1; -; mRNA.
DR EMBL; X07373; CAA30292.1; -; mRNA.
DR EMBL; M24247; AAA59851.1; -; Genomic_DNA.
DR EMBL; M24242; AAA59851.1; JOINED; Genomic_DNA.
DR EMBL; M24243; AAA59851.1; JOINED; Genomic_DNA.
DR EMBL; M24244; AAA59851.1; JOINED; Genomic_DNA.
DR EMBL; M24245; AAA59851.1; JOINED; Genomic_DNA.
DR EMBL; M24246; AAA59851.1; JOINED; Genomic_DNA.
DR EMBL; AF174483; AAF91089.1; -; mRNA.
DR EMBL; AK312044; BAG34981.1; -; mRNA.
DR EMBL; CH471055; EAW64791.1; -; Genomic_DNA.
DR EMBL; BC009790; AAH09790.1; -; mRNA.
DR PIR; B30881; MOHU3V.
DR RefSeq; NP_000249.1; NM_000258.2.
DR UniGene; Hs.517939; -.
DR ProteinModelPortal; P08590; -.
DR SMR; P08590; 49-194.
DR IntAct; P08590; 4.
DR STRING; 9606.ENSP00000292327; -.
DR PhosphoSite; P08590; -.
DR DMDM; 127149; -.
DR UCD-2DPAGE; P08590; -.
DR PaxDb; P08590; -.
DR PRIDE; P08590; -.
DR DNASU; 4634; -.
DR Ensembl; ENST00000292327; ENSP00000292327; ENSG00000160808.
DR Ensembl; ENST00000395869; ENSP00000379210; ENSG00000160808.
DR GeneID; 4634; -.
DR KEGG; hsa:4634; -.
DR UCSC; uc003cql.1; human.
DR CTD; 4634; -.
DR GeneCards; GC03M046899; -.
DR HGNC; HGNC:7584; MYL3.
DR HPA; CAB018662; -.
DR HPA; HPA016564; -.
DR MIM; 160790; gene.
DR MIM; 608751; phenotype.
DR neXtProt; NX_P08590; -.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR PharmGKB; PA31381; -.
DR eggNOG; COG5126; -.
DR HOGENOM; HOG000233018; -.
DR HOVERGEN; HBG012180; -.
DR InParanoid; P08590; -.
DR KO; K12749; -.
DR OMA; RPKEAEF; -.
DR OrthoDB; EOG7HQN9N; -.
DR Reactome; REACT_17044; Muscle contraction.
DR ChiTaRS; MYL3; human.
DR GeneWiki; MYL3; -.
DR GenomeRNAi; 4634; -.
DR NextBio; 17840; -.
DR PMAP-CutDB; P08590; -.
DR PRO; PR:P08590; -.
DR ArrayExpress; P08590; -.
DR Bgee; P08590; -.
DR CleanEx; HS_MYL3; -.
DR Genevestigator; P08590; -.
DR GO; GO:0031672; C:A band; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031674; C:I band; IDA:BHF-UCL.
DR GO; GO:0005859; C:muscle myosin complex; TAS:ProtInc.
DR GO; GO:0003785; F:actin monomer binding; IDA:BHF-UCL.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0003774; F:motor activity; IEA:Ensembl.
DR GO; GO:0032038; F:myosin II heavy chain binding; NAS:BHF-UCL.
DR GO; GO:0008307; F:structural constituent of muscle; TAS:ProtInc.
DR GO; GO:0060048; P:cardiac muscle contraction; IMP:BHF-UCL.
DR GO; GO:0030049; P:muscle filament sliding; TAS:Reactome.
DR GO; GO:0032781; P:positive regulation of ATPase activity; ISS:BHF-UCL.
DR GO; GO:0006942; P:regulation of striated muscle contraction; IMP:BHF-UCL.
DR GO; GO:0002026; P:regulation of the force of heart contraction; IMP:BHF-UCL.
DR GO; GO:0007519; P:skeletal muscle tissue development; IEA:Ensembl.
DR GO; GO:0055010; P:ventricular cardiac muscle tissue morphogenesis; IMP:BHF-UCL.
DR Gene3D; 1.10.238.10; -; 2.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR002048; EF_hand_dom.
DR PROSITE; PS50222; EF_HAND_2; 3.
PE 1: Evidence at protein level;
KW Cardiomyopathy; Complete proteome; Direct protein sequencing;
KW Disease mutation; Methylation; Motor protein; Muscle protein; Myosin;
KW Reference proteome; Repeat.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 195 Myosin light chain 3.
FT /FTId=PRO_0000198696.
FT DOMAIN 49 86 EF-hand 1.
FT DOMAIN 128 163 EF-hand 2.
FT DOMAIN 163 195 EF-hand 3.
FT MOD_RES 2 2 N,N,N-trimethylalanine (Probable).
FT VARIANT 56 56 E -> G (in CMH8).
FT /FTId=VAR_019842.
FT VARIANT 143 143 E -> K (in CMH8; autosomal recessive).
FT /FTId=VAR_019843.
FT VARIANT 149 149 M -> V (in CMH8; with mid-left
FT ventricular chamber thickening).
FT /FTId=VAR_004599.
FT VARIANT 154 154 R -> H (in CMH8; with mid-left
FT ventricular chamber thickening).
FT /FTId=VAR_004600.
FT CONFLICT 171 171 K -> R (in Ref. 5; AAF91089).
SQ SEQUENCE 195 AA; 21932 MW; 306CF328841729DD CRC64;
MAPKKPEPKK DDAKAAPKAA PAPAPPPEPE RPKEVEFDAS KIKIEFTPEQ IEEFKEAFML
FDRTPKCEMK ITYGQCGDVL RALGQNPTQA EVLRVLGKPR QEELNTKMMD FETFLPMLQH
ISKNKDTGTY EDFVEGLRVF DKEGNGTVMG AELRHVLATL GERLTEDEVE KLMAGQEDSN
GCINYEAFVK HIMSS
//
MIM
160790
*RECORD*
*FIELD* NO
160790
*FIELD* TI
*160790 MYOSIN, LIGHT CHAIN 3, ALKALI, VENTRICULAR, SKELETAL, SLOW; MYL3
;;ESSENTIAL LIGHT CHAIN OF MYOSIN;;
read moreELC OF MYOSIN;;
MYOSIN, LIGHT CHAIN 1, SLOW, B; MLC1SB;;
MYOSIN, LIGHT CHAIN 1, VENTRICULAR; MLC1V
*FIELD* TX
The myosin molecule consists of 2 heavy chains and 4 associated light
chains. Two of the light chains are regulatory light chains (RLC)
encoded by the MYL2 gene (160781), and 2 are alkali light chains, or
essential light chains (ELC), encoded by the MYL3 gene. The light chains
stabilize the long alpha-helical neck of the myosin head. Distinct
isoforms of the myosin alkali light chains are present in different
tissues. Their function in striated muscle is only partially understood.
CLONING
Hoffmann et al. (1988) presented the complete nucleotide sequence of
human ventricular myosin light chain-1.
GENE STRUCTURE
Fodor et al. (1989) found that the MYL3 gene has 7 exons, the last of
which is completely untranslated 3-prime sequence.
MAPPING
Darras et al. (1987) and Fodor et al. (1989) used a fragment from the
3-prime end of the human myosin alkali light chain gene, isolated by
screening a partial genomic library with rat skeletal myosin light chain
cDNA, in studies of somatic cell hybrids. The gene was found to map to
3p. In the mouse, the Myl3 gene on distal chromosome 9 codes the
ventricular and slow skeletal muscle isoforms. Other loci in that area,
such as Bgl and Acy, are homologous to genes on human chromosome 3p. It
is possible that the gene mapped by Darras et al. (1987) is the human
homolog of mouse Myl3; thus the designation MYL3 is used for the human
locus.
Using a panel of man-rodent somatic cell hybrids, Cohen-Haguenauer et
al. (1989) mapped the MYL3 gene to chromosome 3. This finding was in
keeping with the assignment of the corresponding gene to mouse
chromosome 9.
GENE FUNCTION
Laugwitz et al. (2001) showed that caspase-3 (600636) activation
directly influences contractile performance of failing ventricular
myocytes, and can be corrected via adenovirus-mediated gene delivery of
the potent caspase inhibitor p35 with a positive impact on
contractility. To determine the molecular mechanism by which activated
caspase-3 causes a deterioration of cardiac function, Moretti et al.
(2002) used a modified yeast 2-hybrid system to screen for caspase-3
interacting proteins of the cardiac cytoskeleton. They identified
ventricular essential myosin light chain (MYL3), symbolized vMLC1 by the
authors, as a target of caspase-3. They demonstrated that MYL3 cleavage
in failing myocardium in vivo was associated with a morphologic
disruption of the organized MYL3 staining of sarcomeres, and with a
reduction in myocyte contractile performance. Adenoviral gene transfer
of p35 in vivo prevented caspase-3 activation and MYL3 cleavage, with
positive impact on contractility. These data suggested that direct
cleavage of the myosin light chain by activated caspase-3 may contribute
to depression of myocyte function by altering crossbridge interaction
between myosin and actin molecules. Therefore, activation of apoptotic
pathways in the heart may lead to contractile dysfunction before cell
death.
MOLECULAR GENETICS
Poetter et al. (1996) analyzed the MYL3 gene in 383 unrelated probands
with hypertrophic cardiomyopathy (see CMH8, 608751) and identified a
heterozygous missense mutation at a conserved residue (M149V;
160790.0001) that segregated with disease in a large 3-generation
family. Linkage analysis of the mutation against hypertrophy gave a lod
score of 6.2 with no recombinants. Six of 13 affected family members had
unusual mid-left ventricular chamber thickening on echocardiography.
Poetter et al. (1996) screened the MYL3 gene in 16 additional CMH
patients with similar mid-left ventricular chamber thickening and
identified a different heterozygous missense mutation (R154H;
160790.0002) in a young boy with massive chamber obstruction. Neither
these nor any other mutations in MYL3 were found in 378 control
chromosomes or 762 chromosomes from unrelated CMH kindreds. Poetter et
al. (1996) also analyzed the MYL2 gene (160761) in CMH patients and
identified 3 different heterozygous mutations in 5 affected individuals,
4 of whom had 'strikingly similar' mid-left ventricular chamber
hypertrophy (see CMH10, 608758).
In 3 sibs of a consanguineous family with early-onset hypertrophic
cardiomyopathy characterized by midcavitary hypertrophy and restrictive
physiology, Olson et al. (2002) performed haplotype analysis using
polymorphic DNA markers spanning genes known to cause hypertrophic
cardiomyopathy. The results suggested that, in keeping with the
consanguineous family history, the phenotype might be an autosomal
recessive form of CMH caused by mutation in MYL3. A homozygous MYL3
mutation, glu143 to lys (E143K; 160790.0003), was subsequently
identified in the proband. The authors suggested that, in contrast to
autosomal dominant CMH mutations in which functional studies demonstrate
a dominant-negative effect, E143K was likely to cause loss of function.
In support of this hypothesis, the authors found that heterozygotes were
unaffected on the basis of electrocardiography and echocardiography. In
addition, this mutation affected an amino acid in a surface-exposed loop
of the essential light chain and was unlikely to disrupt protein
conformation or stability. Site-directed mutagenesis of the
corresponding loop domain (Ho and Chisholm, 1997) had no effect on
binding between myosin heavy and light chains, but significantly reduced
actin-activated ATPase activity and in vitro motility. Thus, Olson et
al. (2002) concluded that this family demonstrated a true autosomal
recessive form of CMH8, characterized by a unique pattern of hypertrophy
previously described in autosomal dominant CMH8.
In the proband from a CMH family previously described by Maron et al.
(1982), in which 6 of 12 affected members had typical asymmetric
hypertrophy and 6 had ventricular septal hypertrophy that was localized
to the apical region of the left ventricle, Arad et al. (2005)
identified heterozygosity for the M149V mutation. Arad et al. (2005)
noted that because the classification of hypertrophy as midcavitary or
apical might in part reflect the evolution of diagnostic imaging
techniques from angiography, by which midcavitary hypertrophy was
historically recognized, to echocardiography and MRI, these may
represent overlapping morphologies.
*FIELD* AV
.0001
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8
MYL3, MET149VAL
In affected members of a large 3-generation family segregating autosomal
dominant hypertrophic cardiomyopathy (CMH8; 608751), Poetter et al.
(1996) identified heterozygosity for an A-G transition in the MYL3 gene,
resulting in a met149-to-val (M149V) substitution at a highly conserved
residue. Six of 13 affected family members had unusual mid-left
ventricular chamber thickening on echocardiography. An in vitro motility
assay of ventricular myosins from 3 mutation-positive individuals
demonstrated an increased rate of actin translocation compared to
controls. Soleus or deltoid muscle biopsies from the same 3 patients
showed myopathic changes and a ragged red fiber pattern characteristic
of primary mitochondrial disease; cytochrome oxidase-positive
subsarcolemmal accumulations were confirmed to be mitochondria by
electron microscopy. The M149V mutation was not found in 378 control
chromosomes or in 762 chromosomes from unrelated CMH kindreds.
In the proband from a CMH family previously described by Maron et al.
(1982), in which 6 of 12 affected members had typical asymmetric
hypertrophy and 6 had ventricular septal hypertrophy that was localized
to the apical region of the left ventricle, Arad et al. (2005)
identified heterozygosity for the M149V mutation. Two members of the
family had died of heart failure, at 35 and 54 years of age,
respectively, and sudden death had occurred in 3 individuals, at ages
26, 33, and 35 years, respectively.
.0002
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8
MYL3, ARG154HIS
In a young boy with hypertrophic cardiomyopathy (CMH8; 608751) and
massive mid-left ventricular chamber obstruction, Poetter et al. (1996)
identified an arg154-to-his (R154H) substitution at a highly conserved
residue in the MYL3 gene. The mutation was not found in 378 control
chromosomes or in 762 chromosomes from unrelated CMH kindreds.
.0003
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8
MYL3, GLU143LYS
Olson et al. (2002) reported a consanguineous family in which 3 sibs had
presented with childhood-onset CMH characterized by midcavitary
left-ventricular hypertrophy (608751). Both parents had completely
normal hearts in their 40s. Mutation screening in a surviving affected
sib revealed a homozygous missense G-to-A point mutation at codon 143 of
the MYL3 gene, resulting in a glutamic acid-to-lysine (E143K)
substitution. Heterozygotes had normal hearts. Sequence alignment of
myosin essential light chains demonstrated high conservation of glutamic
acid at position 143 across species. The E143K mutation was absent from
150 normal control DNA samples. The authors concluded that this was a
true autosomal recessive form of CMH8.
In a 22-year-old woman from El Salvador with cardiomyopathy, Caleshu et
al. (2011) sequenced the exons and exon-intron boundaries of 8 known
cardiomyopathy-associated genes and identified homozygosity for the
E143K mutation in the MYL3 gene. The patient was also found to be
heterozygous for a G57E polymorphism in the MYL2 gene (160781); her
asymptomatic 45-year-old mother, who had a normal transthoracic
echocardiogram, electrocardiogram, and physical examination, was
heterozygous for both the E143K mutation in MYL3 and the G57E
polymorphism in MYL2. The patient, who had a prior diagnosis of
childhood asthma, presented with worsening dyspnea and fatigue over the
previous year, and transthoracic echocardiogram revealed severe biatrial
enlargement with preserved biventricular systolic function and no left
ventricular hypertrophy or valvular disease; Doppler evaluation
suggested advanced left ventricular diastolic dysfunction. Left and
right heart catheterization showed elevated filling pressures
bilaterally, with a prominent y-descent, a suggestion of a
'dip-and-plateau,' and ventricular concordance, all features described
in restrictive cardiomyopathy (RCM). Right ventricular endomyocardial
biopsy revealed marked myocyte hypertrophy and myofiber disarray with
interstitial fibrosis. The patient went on to develop recurrent syncope
and had an automatic implantable cardiac defibrillator placed; she
underwent orthotopic heart transplantation 6 months after diagnosis with
cardiomyopathy.
*FIELD* RF
1. Arad, M.; Penas-Lado, M.; Monserrat, L.; Maron, B. J.; Sherrid,
M.; Ho, C. Y.; Barr, S.; Karim, A.; Olson, T. M.; Kamisago, M.; Seidman,
J. G.; Seidman, C. E.: Gene mutations in apical hypertrophic cardiomyopathy. Circulation 112:
2805-2811, 2005.
2. Caleshu, C.; Sakhuja, R.; Nussbaum, R. L.; Schiller, N. B.; Ursell,
P. C.; Eng, C.; De Marco, T.; McGlothlin, D.; Burchard, E. G.; Rame,
J. E.: Furthering the link between the sarcomere and primary cardiomyopathies:
restrictive cardiomyopathy associated with multiple mutations in genes
previously associated with hypertrophic or dilated cardiomyopathy. Am.
J. Med. Genet. 155A: 2229-2235, 2011.
3. Cohen-Haguenauer, O.; Barton, P. J. R.; Van Cong, N.; Cohen, A.;
Masset, M.; Buckingham, M.; Frezal, J.: Chromosomal assignment of
two myosin alkali light-chain genes encoding the ventricular/slow
skeletal muscle isoform and the atrial/fetal muscle isoform (MYL3,
MYL4). Hum. Genet. 81: 278-282, 1989.
4. Darras, B. T.; Fodor, B.; Vanin, E.; Francke, U.: A human myosin
alkali light chain gene mapped to chromosome 3. (Abstract) Cytogenet.
Cell Genet. 46: 603, 1987.
5. Fodor, W. L.; Darras, B.; Seharaseyon, J.; Falkenthal, S.; Francke,
U.; Vanin, E. F.: Human ventricular/slow twitch myosin alkali light
chain gene characterization, sequence, and chromosomal location. J.
Biol. Chem. 264: 2143-2149, 1989.
6. Ho, G.; Chisholm, R. L.: Substitution mutations in the myosin
essential light chain lead to reduced actin-activated ATPase activity
despite stoichiometric binding to the heavy chain. J. Biol. Chem. 272:
4522-4527, 1997.
7. Hoffmann, E.; Shi, Q. W.; Floroff, M.; Mickle, D. A. G.; Wu, T.-W.;
Olley, P. M.; Jackowski, G.: Molecular cloning and complete nucleotide
sequence of a human ventricular myosin light chain 1. Nucleic Acids
Res. 16: 2353, 1988.
8. Laugwitz, K.-L.; Moretti, A.; Weig, H.-J.; Gillitzer, A.; Pinkernell,
K.; Ott, T.; Pragst, I.; Stadele, C.; Seyfarth, M.; Schomig, A.; Ungerer,
M.: Blocking caspase-activated apoptosis improves contractility in
failing myocardium. Human Gene Ther. 12: 2051-2063, 2001.
9. Maron, B. J.; Bonow, R. O.; Seshagiri, T. N. R.; Roberts, W. C.;
Epstein, S. E.: Hypertrophic cardiomyopathy with ventricular septal
hypertrophy localized to the apical region of the left ventricle (apical
hypertrophic cardiomyopathy). Am. J. Cardiol. 49: 1838-1848, 1982.
10. Moretti, A.; Weig, H.-J.; Ott, T.; Seyfarth, M.; Holthoff, H.-P.;
Grewe, D.; Gillitzer, A.; Bott-Flugel, L.; Schomig, A.; Ungerer, M.;
Laugwitz, K.-L.: Essential myosin light chain as a target for caspase-3
in failing myocardium. Proc. Nat. Acad. Sci. 99: 11860-11865, 2002.
11. Olson, T. M.; Karst, M. L.; Whitby, F. G.; Driscoll, D. J.: Myosin
light chain mutation causes autosomal recessive cardiomyopathy with
mid-cavitary hypertrophy and restrictive physiology. Circulation 105:
2337-2340, 2002.
12. Poetter, K.; Jiang, H.; Hassanzadeh, S.; Master, S. R.; Chang,
A.; Dalakas, M. C.; Rayment, I.; Sellers, J. R.; Fananapazir, L.;
Epstein, N. D.: Mutations in either the essential or regulatory light
chains of myosin are associated with a rare myopathy in human heart
and skeletal muscle. Nature Genet. 13: 63-69, 1996.
*FIELD* CN
Marla J. F. O'Neill - updated: 9/30/2011
Marla J. F. O'Neill - updated: 6/7/2010
Marla J. F. O'Neill - updated: 6/22/2004
Victor A. McKusick - updated: 10/14/2002
Paul Brennan - updated: 6/26/2002
Victor A. McKusick - updated: 6/17/1998
Victor A. McKusick - updated: 8/1/1997
*FIELD* CD
Victor A. McKusick: 8/31/1987
*FIELD* ED
carol: 09/30/2011
terry: 9/30/2011
carol: 6/7/2010
mgross: 2/24/2006
carol: 6/22/2004
carol: 6/14/2004
carol: 3/30/2004
carol: 3/17/2004
tkritzer: 10/28/2002
tkritzer: 10/17/2002
terry: 10/14/2002
alopez: 6/26/2002
carol: 11/9/2001
terry: 11/9/2000
alopez: 10/3/2000
alopez: 4/30/1999
terry: 6/17/1998
mark: 9/26/1997
terry: 8/1/1997
mark: 5/15/1996
terry: 5/14/1996
terry: 5/7/1996
terry: 5/6/1996
supermim: 3/16/1992
carol: 10/11/1991
supermim: 3/20/1990
ddp: 10/27/1989
carol: 5/5/1989
carol: 3/14/1989
*RECORD*
*FIELD* NO
160790
*FIELD* TI
*160790 MYOSIN, LIGHT CHAIN 3, ALKALI, VENTRICULAR, SKELETAL, SLOW; MYL3
;;ESSENTIAL LIGHT CHAIN OF MYOSIN;;
read moreELC OF MYOSIN;;
MYOSIN, LIGHT CHAIN 1, SLOW, B; MLC1SB;;
MYOSIN, LIGHT CHAIN 1, VENTRICULAR; MLC1V
*FIELD* TX
The myosin molecule consists of 2 heavy chains and 4 associated light
chains. Two of the light chains are regulatory light chains (RLC)
encoded by the MYL2 gene (160781), and 2 are alkali light chains, or
essential light chains (ELC), encoded by the MYL3 gene. The light chains
stabilize the long alpha-helical neck of the myosin head. Distinct
isoforms of the myosin alkali light chains are present in different
tissues. Their function in striated muscle is only partially understood.
CLONING
Hoffmann et al. (1988) presented the complete nucleotide sequence of
human ventricular myosin light chain-1.
GENE STRUCTURE
Fodor et al. (1989) found that the MYL3 gene has 7 exons, the last of
which is completely untranslated 3-prime sequence.
MAPPING
Darras et al. (1987) and Fodor et al. (1989) used a fragment from the
3-prime end of the human myosin alkali light chain gene, isolated by
screening a partial genomic library with rat skeletal myosin light chain
cDNA, in studies of somatic cell hybrids. The gene was found to map to
3p. In the mouse, the Myl3 gene on distal chromosome 9 codes the
ventricular and slow skeletal muscle isoforms. Other loci in that area,
such as Bgl and Acy, are homologous to genes on human chromosome 3p. It
is possible that the gene mapped by Darras et al. (1987) is the human
homolog of mouse Myl3; thus the designation MYL3 is used for the human
locus.
Using a panel of man-rodent somatic cell hybrids, Cohen-Haguenauer et
al. (1989) mapped the MYL3 gene to chromosome 3. This finding was in
keeping with the assignment of the corresponding gene to mouse
chromosome 9.
GENE FUNCTION
Laugwitz et al. (2001) showed that caspase-3 (600636) activation
directly influences contractile performance of failing ventricular
myocytes, and can be corrected via adenovirus-mediated gene delivery of
the potent caspase inhibitor p35 with a positive impact on
contractility. To determine the molecular mechanism by which activated
caspase-3 causes a deterioration of cardiac function, Moretti et al.
(2002) used a modified yeast 2-hybrid system to screen for caspase-3
interacting proteins of the cardiac cytoskeleton. They identified
ventricular essential myosin light chain (MYL3), symbolized vMLC1 by the
authors, as a target of caspase-3. They demonstrated that MYL3 cleavage
in failing myocardium in vivo was associated with a morphologic
disruption of the organized MYL3 staining of sarcomeres, and with a
reduction in myocyte contractile performance. Adenoviral gene transfer
of p35 in vivo prevented caspase-3 activation and MYL3 cleavage, with
positive impact on contractility. These data suggested that direct
cleavage of the myosin light chain by activated caspase-3 may contribute
to depression of myocyte function by altering crossbridge interaction
between myosin and actin molecules. Therefore, activation of apoptotic
pathways in the heart may lead to contractile dysfunction before cell
death.
MOLECULAR GENETICS
Poetter et al. (1996) analyzed the MYL3 gene in 383 unrelated probands
with hypertrophic cardiomyopathy (see CMH8, 608751) and identified a
heterozygous missense mutation at a conserved residue (M149V;
160790.0001) that segregated with disease in a large 3-generation
family. Linkage analysis of the mutation against hypertrophy gave a lod
score of 6.2 with no recombinants. Six of 13 affected family members had
unusual mid-left ventricular chamber thickening on echocardiography.
Poetter et al. (1996) screened the MYL3 gene in 16 additional CMH
patients with similar mid-left ventricular chamber thickening and
identified a different heterozygous missense mutation (R154H;
160790.0002) in a young boy with massive chamber obstruction. Neither
these nor any other mutations in MYL3 were found in 378 control
chromosomes or 762 chromosomes from unrelated CMH kindreds. Poetter et
al. (1996) also analyzed the MYL2 gene (160761) in CMH patients and
identified 3 different heterozygous mutations in 5 affected individuals,
4 of whom had 'strikingly similar' mid-left ventricular chamber
hypertrophy (see CMH10, 608758).
In 3 sibs of a consanguineous family with early-onset hypertrophic
cardiomyopathy characterized by midcavitary hypertrophy and restrictive
physiology, Olson et al. (2002) performed haplotype analysis using
polymorphic DNA markers spanning genes known to cause hypertrophic
cardiomyopathy. The results suggested that, in keeping with the
consanguineous family history, the phenotype might be an autosomal
recessive form of CMH caused by mutation in MYL3. A homozygous MYL3
mutation, glu143 to lys (E143K; 160790.0003), was subsequently
identified in the proband. The authors suggested that, in contrast to
autosomal dominant CMH mutations in which functional studies demonstrate
a dominant-negative effect, E143K was likely to cause loss of function.
In support of this hypothesis, the authors found that heterozygotes were
unaffected on the basis of electrocardiography and echocardiography. In
addition, this mutation affected an amino acid in a surface-exposed loop
of the essential light chain and was unlikely to disrupt protein
conformation or stability. Site-directed mutagenesis of the
corresponding loop domain (Ho and Chisholm, 1997) had no effect on
binding between myosin heavy and light chains, but significantly reduced
actin-activated ATPase activity and in vitro motility. Thus, Olson et
al. (2002) concluded that this family demonstrated a true autosomal
recessive form of CMH8, characterized by a unique pattern of hypertrophy
previously described in autosomal dominant CMH8.
In the proband from a CMH family previously described by Maron et al.
(1982), in which 6 of 12 affected members had typical asymmetric
hypertrophy and 6 had ventricular septal hypertrophy that was localized
to the apical region of the left ventricle, Arad et al. (2005)
identified heterozygosity for the M149V mutation. Arad et al. (2005)
noted that because the classification of hypertrophy as midcavitary or
apical might in part reflect the evolution of diagnostic imaging
techniques from angiography, by which midcavitary hypertrophy was
historically recognized, to echocardiography and MRI, these may
represent overlapping morphologies.
*FIELD* AV
.0001
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8
MYL3, MET149VAL
In affected members of a large 3-generation family segregating autosomal
dominant hypertrophic cardiomyopathy (CMH8; 608751), Poetter et al.
(1996) identified heterozygosity for an A-G transition in the MYL3 gene,
resulting in a met149-to-val (M149V) substitution at a highly conserved
residue. Six of 13 affected family members had unusual mid-left
ventricular chamber thickening on echocardiography. An in vitro motility
assay of ventricular myosins from 3 mutation-positive individuals
demonstrated an increased rate of actin translocation compared to
controls. Soleus or deltoid muscle biopsies from the same 3 patients
showed myopathic changes and a ragged red fiber pattern characteristic
of primary mitochondrial disease; cytochrome oxidase-positive
subsarcolemmal accumulations were confirmed to be mitochondria by
electron microscopy. The M149V mutation was not found in 378 control
chromosomes or in 762 chromosomes from unrelated CMH kindreds.
In the proband from a CMH family previously described by Maron et al.
(1982), in which 6 of 12 affected members had typical asymmetric
hypertrophy and 6 had ventricular septal hypertrophy that was localized
to the apical region of the left ventricle, Arad et al. (2005)
identified heterozygosity for the M149V mutation. Two members of the
family had died of heart failure, at 35 and 54 years of age,
respectively, and sudden death had occurred in 3 individuals, at ages
26, 33, and 35 years, respectively.
.0002
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8
MYL3, ARG154HIS
In a young boy with hypertrophic cardiomyopathy (CMH8; 608751) and
massive mid-left ventricular chamber obstruction, Poetter et al. (1996)
identified an arg154-to-his (R154H) substitution at a highly conserved
residue in the MYL3 gene. The mutation was not found in 378 control
chromosomes or in 762 chromosomes from unrelated CMH kindreds.
.0003
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8
MYL3, GLU143LYS
Olson et al. (2002) reported a consanguineous family in which 3 sibs had
presented with childhood-onset CMH characterized by midcavitary
left-ventricular hypertrophy (608751). Both parents had completely
normal hearts in their 40s. Mutation screening in a surviving affected
sib revealed a homozygous missense G-to-A point mutation at codon 143 of
the MYL3 gene, resulting in a glutamic acid-to-lysine (E143K)
substitution. Heterozygotes had normal hearts. Sequence alignment of
myosin essential light chains demonstrated high conservation of glutamic
acid at position 143 across species. The E143K mutation was absent from
150 normal control DNA samples. The authors concluded that this was a
true autosomal recessive form of CMH8.
In a 22-year-old woman from El Salvador with cardiomyopathy, Caleshu et
al. (2011) sequenced the exons and exon-intron boundaries of 8 known
cardiomyopathy-associated genes and identified homozygosity for the
E143K mutation in the MYL3 gene. The patient was also found to be
heterozygous for a G57E polymorphism in the MYL2 gene (160781); her
asymptomatic 45-year-old mother, who had a normal transthoracic
echocardiogram, electrocardiogram, and physical examination, was
heterozygous for both the E143K mutation in MYL3 and the G57E
polymorphism in MYL2. The patient, who had a prior diagnosis of
childhood asthma, presented with worsening dyspnea and fatigue over the
previous year, and transthoracic echocardiogram revealed severe biatrial
enlargement with preserved biventricular systolic function and no left
ventricular hypertrophy or valvular disease; Doppler evaluation
suggested advanced left ventricular diastolic dysfunction. Left and
right heart catheterization showed elevated filling pressures
bilaterally, with a prominent y-descent, a suggestion of a
'dip-and-plateau,' and ventricular concordance, all features described
in restrictive cardiomyopathy (RCM). Right ventricular endomyocardial
biopsy revealed marked myocyte hypertrophy and myofiber disarray with
interstitial fibrosis. The patient went on to develop recurrent syncope
and had an automatic implantable cardiac defibrillator placed; she
underwent orthotopic heart transplantation 6 months after diagnosis with
cardiomyopathy.
*FIELD* RF
1. Arad, M.; Penas-Lado, M.; Monserrat, L.; Maron, B. J.; Sherrid,
M.; Ho, C. Y.; Barr, S.; Karim, A.; Olson, T. M.; Kamisago, M.; Seidman,
J. G.; Seidman, C. E.: Gene mutations in apical hypertrophic cardiomyopathy. Circulation 112:
2805-2811, 2005.
2. Caleshu, C.; Sakhuja, R.; Nussbaum, R. L.; Schiller, N. B.; Ursell,
P. C.; Eng, C.; De Marco, T.; McGlothlin, D.; Burchard, E. G.; Rame,
J. E.: Furthering the link between the sarcomere and primary cardiomyopathies:
restrictive cardiomyopathy associated with multiple mutations in genes
previously associated with hypertrophic or dilated cardiomyopathy. Am.
J. Med. Genet. 155A: 2229-2235, 2011.
3. Cohen-Haguenauer, O.; Barton, P. J. R.; Van Cong, N.; Cohen, A.;
Masset, M.; Buckingham, M.; Frezal, J.: Chromosomal assignment of
two myosin alkali light-chain genes encoding the ventricular/slow
skeletal muscle isoform and the atrial/fetal muscle isoform (MYL3,
MYL4). Hum. Genet. 81: 278-282, 1989.
4. Darras, B. T.; Fodor, B.; Vanin, E.; Francke, U.: A human myosin
alkali light chain gene mapped to chromosome 3. (Abstract) Cytogenet.
Cell Genet. 46: 603, 1987.
5. Fodor, W. L.; Darras, B.; Seharaseyon, J.; Falkenthal, S.; Francke,
U.; Vanin, E. F.: Human ventricular/slow twitch myosin alkali light
chain gene characterization, sequence, and chromosomal location. J.
Biol. Chem. 264: 2143-2149, 1989.
6. Ho, G.; Chisholm, R. L.: Substitution mutations in the myosin
essential light chain lead to reduced actin-activated ATPase activity
despite stoichiometric binding to the heavy chain. J. Biol. Chem. 272:
4522-4527, 1997.
7. Hoffmann, E.; Shi, Q. W.; Floroff, M.; Mickle, D. A. G.; Wu, T.-W.;
Olley, P. M.; Jackowski, G.: Molecular cloning and complete nucleotide
sequence of a human ventricular myosin light chain 1. Nucleic Acids
Res. 16: 2353, 1988.
8. Laugwitz, K.-L.; Moretti, A.; Weig, H.-J.; Gillitzer, A.; Pinkernell,
K.; Ott, T.; Pragst, I.; Stadele, C.; Seyfarth, M.; Schomig, A.; Ungerer,
M.: Blocking caspase-activated apoptosis improves contractility in
failing myocardium. Human Gene Ther. 12: 2051-2063, 2001.
9. Maron, B. J.; Bonow, R. O.; Seshagiri, T. N. R.; Roberts, W. C.;
Epstein, S. E.: Hypertrophic cardiomyopathy with ventricular septal
hypertrophy localized to the apical region of the left ventricle (apical
hypertrophic cardiomyopathy). Am. J. Cardiol. 49: 1838-1848, 1982.
10. Moretti, A.; Weig, H.-J.; Ott, T.; Seyfarth, M.; Holthoff, H.-P.;
Grewe, D.; Gillitzer, A.; Bott-Flugel, L.; Schomig, A.; Ungerer, M.;
Laugwitz, K.-L.: Essential myosin light chain as a target for caspase-3
in failing myocardium. Proc. Nat. Acad. Sci. 99: 11860-11865, 2002.
11. Olson, T. M.; Karst, M. L.; Whitby, F. G.; Driscoll, D. J.: Myosin
light chain mutation causes autosomal recessive cardiomyopathy with
mid-cavitary hypertrophy and restrictive physiology. Circulation 105:
2337-2340, 2002.
12. Poetter, K.; Jiang, H.; Hassanzadeh, S.; Master, S. R.; Chang,
A.; Dalakas, M. C.; Rayment, I.; Sellers, J. R.; Fananapazir, L.;
Epstein, N. D.: Mutations in either the essential or regulatory light
chains of myosin are associated with a rare myopathy in human heart
and skeletal muscle. Nature Genet. 13: 63-69, 1996.
*FIELD* CN
Marla J. F. O'Neill - updated: 9/30/2011
Marla J. F. O'Neill - updated: 6/7/2010
Marla J. F. O'Neill - updated: 6/22/2004
Victor A. McKusick - updated: 10/14/2002
Paul Brennan - updated: 6/26/2002
Victor A. McKusick - updated: 6/17/1998
Victor A. McKusick - updated: 8/1/1997
*FIELD* CD
Victor A. McKusick: 8/31/1987
*FIELD* ED
carol: 09/30/2011
terry: 9/30/2011
carol: 6/7/2010
mgross: 2/24/2006
carol: 6/22/2004
carol: 6/14/2004
carol: 3/30/2004
carol: 3/17/2004
tkritzer: 10/28/2002
tkritzer: 10/17/2002
terry: 10/14/2002
alopez: 6/26/2002
carol: 11/9/2001
terry: 11/9/2000
alopez: 10/3/2000
alopez: 4/30/1999
terry: 6/17/1998
mark: 9/26/1997
terry: 8/1/1997
mark: 5/15/1996
terry: 5/14/1996
terry: 5/7/1996
terry: 5/6/1996
supermim: 3/16/1992
carol: 10/11/1991
supermim: 3/20/1990
ddp: 10/27/1989
carol: 5/5/1989
carol: 3/14/1989
MIM
608751
*RECORD*
*FIELD* NO
608751
*FIELD* TI
#608751 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8; CMH8
;;CARDIOMYOPATHY, HYPERTROPHIC, MID-LEFT VENTRICULAR CHAMBER TYPE, 1
read more*FIELD* TX
A number sign (#) is used with this entry because familial hypertrophic
cardiomyopathy-8 (CMH8) is caused by homozygous or heterozygous mutation
in the MYL3 gene (160790).
For a general phenotypic description and a discussion of genetic
heterogeneity of hypertrophic cardiomyopathy, see CMH1 (192600).
CLINICAL FEATURES
Poetter et al. (1996) studied a large 3-generation family segregating
autosomal dominant hypertrophic cardiomyopathy (CMH), in which 6 of 13
affected individuals had a rare variant of cardiac hypertrophy that
involved mid-left ventricular chamber thickening apparent in the left
ventriculogram and was associated with a pressure gradient detectable by
Doppler echocardiography. Massive hypertrophy of the cardiac papillary
muscles and adjacent ventricular tissue was present, causing a
midcavitary obstruction. Soleus or deltoid muscle biopsies from 3
patients showed myopathic changes and a ragged red fiber pattern
characteristic of primary mitochondrial disease; cytochrome
oxidase-positive subsarcolemmal accumulations were confirmed to be
mitochondria by electron microscopy. Poetter et al. (1996) also
ascertained a young boy with massive mid-left ventricular chamber
obstruction, and stated that it was even more rare to find this
phenotype in a child.
Autosomal recessive inheritance of CMH8 was suspected in a 5-generation
consanguineous family reported by Olson et al. (2002). Three male sibs,
the products of a second-cousin marriage, developed a cardiomyopathy in
the second decade of life. Two died within 2 years of diagnosis. The
surviving affected child, the proband, had left ventricular hypertrophy
and repolarization abnormalities on his ECG. His echocardiogram
demonstrated midcavitary left ventricular hypertrophy with mild
obstruction during systole. Restrictive physiology was suggested by mild
pulmonary hypertension and severe biatrial enlargement. Similar
investigations in the child's parents, paternal grandparents, and
asymptomatic sister were all normal.
MOLECULAR GENETICS
Poetter et al. (1996) analyzed the MYL3 gene (160790) in 383 unrelated
probands with hypertrophic cardiomyopathy and identified a heterozygous
missense mutation at a conserved residue (M149V; 160790.0001) that
segregated with disease in a large 3-generation family. Linkage analysis
of the mutation against hypertrophy gave a lod score of 6.2 with no
recombinants. Six of 13 affected family members had unusual mid-left
ventricular chamber thickening on echocardiography, thus Poetter et al.
(1996) screened an additional 16 unrelated CMH patients with similar
mid-left ventricular chamber thickening for mutations in MYL3 and
identified a different heterozygous missense mutation (R154H;
160790.0002) in a young boy with massive chamber obstruction. Neither
these mutations nor any other mutations in MYL3 were identified in 378
control chromosomes or 762 chromosomes from unrelated CMH kindreds.
In a consanguineous family in which 3 sibs had early-onset hypertrophic
cardiomyopathy characterized by midcavitary hypertrophy and restrictive
physiology, Olson et al. (2002) performed haplotype analysis using
polymorphic DNA markers spanning genes known to cause hypertrophic
cardiomyopathy. The results suggested that, in keeping with the
consanguineous family history, the phenotype might be an autosomal
recessive form of CMH caused by mutation in MYL3. Homozygosity for a
glu143-to-lys (E143K; 160790.0003) substitution in MYL3 was subsequently
identified in the proband. The authors suggested that, in contrast to
autosomal dominant CMH mutations in which functional studies demonstrate
a dominant-negative effect, E143K was likely to cause loss of function.
In support of this hypothesis, the authors found that heterozygotes were
unaffected on the basis of electrocardiography and echocardiography.
Olson et al. (2002) concluded that this family demonstrated a true
autosomal recessive form of CMH8, characterized by a unique pattern of
hypertrophy previously described in autosomal dominant CMH8.
In the proband from a CMH family previously described by Maron et al.
(1982), in which 6 of 12 affected members had prototypic asymmetric
hypertrophy and 6 had ventricular septal hypertrophy that was localized
to the apical region of the left ventricle, Arad et al. (2005)
identified heterozygosity for the same M149V mutation that had
previously been found in patients with mid-left ventricular chamber
hypertrophy (Poetter et al., 1996). Arad et al. (2005) noted that
because the classification of hypertrophy as midcavitary or apical might
in part reflect the evolution of diagnostic imaging techniques from
angiography, by which midcavitary hypertrophy was historically
recognized, to echocardiography and MRI, these may represent overlapping
morphologies.
*FIELD* RF
1. Arad, M.; Penas-Lado, M.; Monserrat, L.; Maron, B. J.; Sherrid,
M.; Ho, C. Y.; Barr, S.; Karim, A.; Olson, T. M.; Kamisago, M.; Seidman,
J. G.; Seidman, C. E.: Gene mutations in apical hypertrophic cardiomyopathy. Circulation 112:
2805-2811, 2005.
2. Maron, B. J.; Bonow, R. O.; Seshagiri, T. N. R.; Roberts, W. C.;
Epstein, S. E.: Hypertrophic cardiomyopathy with ventricular septal
hypertrophy localized to the apical region of the left ventricle (apical
hypertrophic cardiomyopathy). Am. J. Cardiol. 49: 1838-1848, 1982.
3. Olson, T. M.; Karst, M. L.; Whitby, F. G.; Driscoll, D. J.: Myosin
light chain mutation causes autosomal recessive cardiomyopathy with
mid-cavitary hypertrophy and restrictive physiology. Circulation 105:
2337-2340, 2002.
4. Poetter, K.; Jiang, H.; Hassanzadeh, S.; Master, S. R.; Chang,
A.; Dalakas, M. C.; Rayment, I.; Sellers, J. R.; Fananapazir, L.;
Epstein, N. D.: Mutations in either the essential or regulatory light
chains of myosin are associated with a rare myopathy in human heart
and skeletal muscle. Nature Genet. 13: 63-69, 1996.
*FIELD* CN
Marla J. F. O'Neill - updated: 6/7/2010
*FIELD* CD
Marla J. F. O'Neill: 6/21/2004
*FIELD* ED
carol: 09/04/2013
carol: 6/7/2010
carol: 8/12/2005
carol: 6/22/2004
*RECORD*
*FIELD* NO
608751
*FIELD* TI
#608751 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8; CMH8
;;CARDIOMYOPATHY, HYPERTROPHIC, MID-LEFT VENTRICULAR CHAMBER TYPE, 1
read more*FIELD* TX
A number sign (#) is used with this entry because familial hypertrophic
cardiomyopathy-8 (CMH8) is caused by homozygous or heterozygous mutation
in the MYL3 gene (160790).
For a general phenotypic description and a discussion of genetic
heterogeneity of hypertrophic cardiomyopathy, see CMH1 (192600).
CLINICAL FEATURES
Poetter et al. (1996) studied a large 3-generation family segregating
autosomal dominant hypertrophic cardiomyopathy (CMH), in which 6 of 13
affected individuals had a rare variant of cardiac hypertrophy that
involved mid-left ventricular chamber thickening apparent in the left
ventriculogram and was associated with a pressure gradient detectable by
Doppler echocardiography. Massive hypertrophy of the cardiac papillary
muscles and adjacent ventricular tissue was present, causing a
midcavitary obstruction. Soleus or deltoid muscle biopsies from 3
patients showed myopathic changes and a ragged red fiber pattern
characteristic of primary mitochondrial disease; cytochrome
oxidase-positive subsarcolemmal accumulations were confirmed to be
mitochondria by electron microscopy. Poetter et al. (1996) also
ascertained a young boy with massive mid-left ventricular chamber
obstruction, and stated that it was even more rare to find this
phenotype in a child.
Autosomal recessive inheritance of CMH8 was suspected in a 5-generation
consanguineous family reported by Olson et al. (2002). Three male sibs,
the products of a second-cousin marriage, developed a cardiomyopathy in
the second decade of life. Two died within 2 years of diagnosis. The
surviving affected child, the proband, had left ventricular hypertrophy
and repolarization abnormalities on his ECG. His echocardiogram
demonstrated midcavitary left ventricular hypertrophy with mild
obstruction during systole. Restrictive physiology was suggested by mild
pulmonary hypertension and severe biatrial enlargement. Similar
investigations in the child's parents, paternal grandparents, and
asymptomatic sister were all normal.
MOLECULAR GENETICS
Poetter et al. (1996) analyzed the MYL3 gene (160790) in 383 unrelated
probands with hypertrophic cardiomyopathy and identified a heterozygous
missense mutation at a conserved residue (M149V; 160790.0001) that
segregated with disease in a large 3-generation family. Linkage analysis
of the mutation against hypertrophy gave a lod score of 6.2 with no
recombinants. Six of 13 affected family members had unusual mid-left
ventricular chamber thickening on echocardiography, thus Poetter et al.
(1996) screened an additional 16 unrelated CMH patients with similar
mid-left ventricular chamber thickening for mutations in MYL3 and
identified a different heterozygous missense mutation (R154H;
160790.0002) in a young boy with massive chamber obstruction. Neither
these mutations nor any other mutations in MYL3 were identified in 378
control chromosomes or 762 chromosomes from unrelated CMH kindreds.
In a consanguineous family in which 3 sibs had early-onset hypertrophic
cardiomyopathy characterized by midcavitary hypertrophy and restrictive
physiology, Olson et al. (2002) performed haplotype analysis using
polymorphic DNA markers spanning genes known to cause hypertrophic
cardiomyopathy. The results suggested that, in keeping with the
consanguineous family history, the phenotype might be an autosomal
recessive form of CMH caused by mutation in MYL3. Homozygosity for a
glu143-to-lys (E143K; 160790.0003) substitution in MYL3 was subsequently
identified in the proband. The authors suggested that, in contrast to
autosomal dominant CMH mutations in which functional studies demonstrate
a dominant-negative effect, E143K was likely to cause loss of function.
In support of this hypothesis, the authors found that heterozygotes were
unaffected on the basis of electrocardiography and echocardiography.
Olson et al. (2002) concluded that this family demonstrated a true
autosomal recessive form of CMH8, characterized by a unique pattern of
hypertrophy previously described in autosomal dominant CMH8.
In the proband from a CMH family previously described by Maron et al.
(1982), in which 6 of 12 affected members had prototypic asymmetric
hypertrophy and 6 had ventricular septal hypertrophy that was localized
to the apical region of the left ventricle, Arad et al. (2005)
identified heterozygosity for the same M149V mutation that had
previously been found in patients with mid-left ventricular chamber
hypertrophy (Poetter et al., 1996). Arad et al. (2005) noted that
because the classification of hypertrophy as midcavitary or apical might
in part reflect the evolution of diagnostic imaging techniques from
angiography, by which midcavitary hypertrophy was historically
recognized, to echocardiography and MRI, these may represent overlapping
morphologies.
*FIELD* RF
1. Arad, M.; Penas-Lado, M.; Monserrat, L.; Maron, B. J.; Sherrid,
M.; Ho, C. Y.; Barr, S.; Karim, A.; Olson, T. M.; Kamisago, M.; Seidman,
J. G.; Seidman, C. E.: Gene mutations in apical hypertrophic cardiomyopathy. Circulation 112:
2805-2811, 2005.
2. Maron, B. J.; Bonow, R. O.; Seshagiri, T. N. R.; Roberts, W. C.;
Epstein, S. E.: Hypertrophic cardiomyopathy with ventricular septal
hypertrophy localized to the apical region of the left ventricle (apical
hypertrophic cardiomyopathy). Am. J. Cardiol. 49: 1838-1848, 1982.
3. Olson, T. M.; Karst, M. L.; Whitby, F. G.; Driscoll, D. J.: Myosin
light chain mutation causes autosomal recessive cardiomyopathy with
mid-cavitary hypertrophy and restrictive physiology. Circulation 105:
2337-2340, 2002.
4. Poetter, K.; Jiang, H.; Hassanzadeh, S.; Master, S. R.; Chang,
A.; Dalakas, M. C.; Rayment, I.; Sellers, J. R.; Fananapazir, L.;
Epstein, N. D.: Mutations in either the essential or regulatory light
chains of myosin are associated with a rare myopathy in human heart
and skeletal muscle. Nature Genet. 13: 63-69, 1996.
*FIELD* CN
Marla J. F. O'Neill - updated: 6/7/2010
*FIELD* CD
Marla J. F. O'Neill: 6/21/2004
*FIELD* ED
carol: 09/04/2013
carol: 6/7/2010
carol: 8/12/2005
carol: 6/22/2004