Full text data of ACTC1
ACTC1
(ACTC)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Actin, alpha cardiac muscle 1 (Alpha-cardiac actin; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Actin, alpha cardiac muscle 1 (Alpha-cardiac actin; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P68032
ID ACTC_HUMAN Reviewed; 377 AA.
AC P68032; P04270;
DT 20-MAR-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 20-MAR-1987, sequence version 1.
DT 22-JAN-2014, entry version 103.
DE RecName: Full=Actin, alpha cardiac muscle 1;
DE AltName: Full=Alpha-cardiac actin;
DE Flags: Precursor;
GN Name=ACTC1; Synonyms=ACTC;
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 [GENOMIC DNA].
RX PubMed=6310553; DOI=10.1073/pnas.79.19.5901;
RA Hamada H., Petrino M.G., Kakunaga T.;
RT "Molecular structure and evolutionary origin of human cardiac muscle
RT actin gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 79:5901-5905(1982).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=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 [4]
RP METHYLATION AT LYS-86, AND DEMETHYLATION BY ALKBH4.
RX PubMed=23673617; DOI=10.1038/ncomms2863;
RA Li M.M., Nilsen A., Shi Y., Fusser M., Ding Y.H., Fu Y., Liu B.,
RA Niu Y., Wu Y.S., Huang C.M., Olofsson M., Jin K.X., Lv Y., Xu X.Z.,
RA He C., Dong M.Q., Rendtlew Danielsen J.M., Klungland A., Yang Y.G.;
RT "ALKBH4-dependent demethylation of actin regulates actomyosin
RT dynamics.";
RL Nat. Commun. 4:1832-1832(2013).
RN [5]
RP VARIANTS CMD1R HIS-314 AND GLY-363.
RX PubMed=9563954; DOI=10.1126/science.280.5364.750;
RA Olson T.M., Michels V.V., Thibodeau S.N., Tai Y.-S., Keating M.T.;
RT "Actin mutations in dilated cardiomyopathy, a heritable form of heart
RT failure.";
RL Science 280:750-752(1998).
RN [6]
RP VARIANT CMH11 SER-297.
RX PubMed=10330430; DOI=10.1172/JCI6460;
RA Mogensen J., Klausen I.C., Pedersen A.K., Egeblad H., Bross P.,
RA Kruse T.A., Gregersen N., Hansen P.S., Baandrup U., Boerglum A.D.;
RT "Alpha-cardiac actin is a novel disease gene in familial hypertrophic
RT cardiomyopathy.";
RL J. Clin. Invest. 103:R39-R43(1999).
RN [7]
RP VARIANTS CMH11 LYS-101; ALA-166 AND PRO-333.
RX PubMed=10966831; DOI=10.1006/jmcc.2000.1204;
RA Olson T.M., Doan T.P., Kishimoto N.Y., Whitby F.G., Ackerman M.J.,
RA Fananapazir L.;
RT "Inherited and de novo mutations in the cardiac actin gene cause
RT hypertrophic cardiomyopathy.";
RL J. Mol. Cell. Cardiol. 32:1687-1694(2000).
RN [8]
RP VARIANTS CMH11 CYS-168 AND LEU-307.
RX PubMed=14729850; DOI=10.1136/jmg.2003.010447;
RA Mogensen J., Perrot A., Andersen P.S., Havndrup O., Klausen I.C.,
RA Christiansen M., Bross P., Egeblad H., Bundgaard H., Osterziel K.J.,
RA Haltern G., Lapp H., Reinecke P., Gregersen N., Borglum A.D.;
RT "Clinical and genetic characteristics of alpha cardiac actin gene
RT mutations in hypertrophic cardiomyopathy.";
RL J. Med. Genet. 41:E10-E10(2004).
RN [9]
RP VARIANT ASD5 VAL-125, AND CHARACTERIZATION OF VARIANT ASD5 VAL-125.
RX PubMed=17947298; DOI=10.1093/hmg/ddm302;
RA Matsson H., Eason J., Bookwalter C.S., Klar J., Gustavsson P.,
RA Sunnegardh J., Enell H., Jonzon A., Vikkula M., Gutierrez I.,
RA Granados-Riveron J., Pope M., Bu'Lock F., Cox J., Robinson T.E.,
RA Song F., Brook D.J., Marston S., Trybus K.M., Dahl N.;
RT "Alpha-cardiac actin mutations produce atrial septal defects.";
RL Hum. Mol. Genet. 17:256-265(2008).
RN [10]
RP VARIANTS CMH11 TYR-90 AND CYS-97.
RX PubMed=18403758; DOI=10.1056/NEJMoa075463;
RA Morita H., Rehm H.L., Menesses A., McDonough B., Roberts A.E.,
RA Kucherlapati R., Towbin J.A., Seidman J.G., Seidman C.E.;
RT "Shared genetic causes of cardiac hypertrophy in children and
RT adults.";
RL N. Engl. J. Med. 358:1899-1908(2008).
CC -!- FUNCTION: Actins are highly conserved proteins that are involved
CC in various types of cell motility and are ubiquitously expressed
CC in all eukaryotic cells.
CC -!- SUBUNIT: Polymerization of globular actin (G-actin) leads to a
CC structural filament (F-actin) in the form of a two-stranded helix.
CC Each actin can bind to 4 others.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton.
CC -!- PTM: Oxidation of Met-46 and Met-49 by MICALs (MICAL1, MICAL2 or
CC MICAL3) to form methionine sulfoxide promotes actin filament
CC depolymerization. MICAL1 and MICAL2 produce the (R)-S-oxide form.
CC The (R)-S-oxide form is reverted by MSRB1 and MSRB2, which promote
CC actin repolymerization (By similarity).
CC -!- PTM: Monomethylation at Lys-86 (K84me1) regulates actin-myosin
CC interaction and actomyosin-dependent processes. Demethylation by
CC ALKBH4 is required for maintaining actomyosin dynamics supporting
CC normal cleavage furrow ingression during cytokinesis and cell
CC migration.
CC -!- DISEASE: Cardiomyopathy, dilated 1R (CMD1R) [MIM:613424]: A
CC disorder characterized by ventricular dilation and impaired
CC systolic function, resulting in congestive heart failure and
CC arrhythmia. Patients are at risk of premature death. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Cardiomyopathy, familial hypertrophic 11 (CMH11)
CC [MIM:612098]: 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 Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Atrial septal defect 5 (ASD5) [MIM:612794]: A congenital
CC heart malformation characterized by incomplete closure of the wall
CC between the atria resulting in blood flow from the left to the
CC right atria. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- MISCELLANEOUS: In vertebrates 3 main groups of actin isoforms,
CC alpha, beta and gamma have been identified. The alpha actins are
CC found in muscle tissues and are a major constituent of the
CC contractile apparatus. The beta and gamma actins coexist in most
CC cell types as components of the cytoskeleton and as mediators of
CC internal cell motility.
CC -!- SIMILARITY: Belongs to the actin family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ACTC1";
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; J00073; AAB59619.1; -; Genomic_DNA.
DR EMBL; J00070; AAB59619.1; JOINED; Genomic_DNA.
DR EMBL; J00071; AAB59619.1; JOINED; Genomic_DNA.
DR EMBL; J00072; AAB59619.1; JOINED; Genomic_DNA.
DR EMBL; CR541795; CAG46594.1; -; mRNA.
DR EMBL; BC009978; AAH09978.1; -; mRNA.
DR PIR; A02998; ATHUC.
DR RefSeq; NP_005150.1; NM_005159.4.
DR UniGene; Hs.118127; -.
DR ProteinModelPortal; P68032; -.
DR SMR; P68032; 6-377.
DR IntAct; P68032; 13.
DR MINT; MINT-1425728; -.
DR STRING; 9606.ENSP00000290378; -.
DR PhosphoSite; P68032; -.
DR DMDM; 54036697; -.
DR REPRODUCTION-2DPAGE; P68032; -.
DR PaxDb; P68032; -.
DR PRIDE; P68032; -.
DR DNASU; 70; -.
DR Ensembl; ENST00000290378; ENSP00000290378; ENSG00000159251.
DR GeneID; 70; -.
DR KEGG; hsa:70; -.
DR UCSC; uc001ziu.1; human.
DR CTD; 70; -.
DR GeneCards; GC15M035080; -.
DR HGNC; HGNC:143; ACTC1.
DR HPA; CAB037330; -.
DR HPA; HPA041271; -.
DR MIM; 102540; gene.
DR MIM; 612098; phenotype.
DR MIM; 612794; phenotype.
DR MIM; 613424; phenotype.
DR neXtProt; NX_P68032; -.
DR Orphanet; 99103; Atrial septal defect, ostium secundum type.
DR Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR Orphanet; 54260; Left ventricular noncompaction.
DR PharmGKB; PA162375571; -.
DR eggNOG; COG5277; -.
DR HOGENOM; HOG000233340; -.
DR HOVERGEN; HBG003771; -.
DR InParanoid; P68032; -.
DR KO; K12314; -.
DR OMA; MGSANKT; -.
DR OrthoDB; EOG72RMZ1; -.
DR PhylomeDB; P68032; -.
DR Reactome; REACT_17044; Muscle contraction.
DR SignaLink; P68032; -.
DR GeneWiki; ACTC1; -.
DR GenomeRNAi; 70; -.
DR NextBio; 275; -.
DR PRO; PR:P68032; -.
DR ArrayExpress; P68032; -.
DR Bgee; P68032; -.
DR CleanEx; HS_ACTC1; -.
DR Genevestigator; P68032; -.
DR GO; GO:0042643; C:actomyosin, actin portion; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0031674; C:I band; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0016887; F:ATPase activity; IDA:UniProtKB.
DR GO; GO:0017022; F:myosin binding; IDA:BHF-UCL.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0060048; P:cardiac muscle contraction; IEA:Ensembl.
DR GO; GO:0055008; P:cardiac muscle tissue morphogenesis; ISS:UniProtKB.
DR GO; GO:0055003; P:cardiac myofibril assembly; ISS:UniProtKB.
DR GO; GO:0060047; P:heart contraction; IMP:UniProtKB.
DR GO; GO:0030049; P:muscle filament sliding; TAS:Reactome.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0030240; P:skeletal muscle thin filament assembly; ISS:UniProtKB.
DR InterPro; IPR004000; Actin-related.
DR InterPro; IPR020902; Actin/actin-like_CS.
DR InterPro; IPR004001; Actin_CS.
DR PANTHER; PTHR11937; PTHR11937; 1.
DR Pfam; PF00022; Actin; 1.
DR PRINTS; PR00190; ACTIN.
DR SMART; SM00268; ACTIN; 1.
DR PROSITE; PS00406; ACTINS_1; 1.
DR PROSITE; PS00432; ACTINS_2; 1.
DR PROSITE; PS01132; ACTINS_ACT_LIKE; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Atrial septal defect; Cardiomyopathy;
KW Complete proteome; Cytoplasm; Cytoskeleton; Disease mutation;
KW Methylation; Muscle protein; Nucleotide-binding; Oxidation;
KW Reference proteome.
FT PROPEP 1 2 Removed in mature form (By similarity).
FT /FTId=PRO_0000000812.
FT CHAIN 3 377 Actin, alpha cardiac muscle 1.
FT /FTId=PRO_0000000813.
FT MOD_RES 3 3 N-acetylaspartate (By similarity).
FT MOD_RES 46 46 Methionine (R)-sulfoxide (By similarity).
FT MOD_RES 49 49 Methionine (R)-sulfoxide (By similarity).
FT MOD_RES 75 75 Tele-methylhistidine (By similarity).
FT MOD_RES 86 86 N6-methyllysine.
FT VARIANT 90 90 H -> Y (in CMH11).
FT /FTId=VAR_045924.
FT VARIANT 97 97 R -> C (in CMH11).
FT /FTId=VAR_045925.
FT VARIANT 101 101 E -> K (in CMH11).
FT /FTId=VAR_012857.
FT VARIANT 125 125 M -> V (in ASD5; reduced affinity for
FT myosin; normal actin filament
FT polymerization ability; normal actomyosin
FT motor function).
FT /FTId=VAR_046502.
FT VARIANT 166 166 P -> A (in CMH11).
FT /FTId=VAR_012858.
FT VARIANT 168 168 Y -> C (in CMH11).
FT /FTId=VAR_046503.
FT VARIANT 297 297 A -> S (in CMH11).
FT /FTId=VAR_012859.
FT VARIANT 307 307 M -> L (in CMH11).
FT /FTId=VAR_046504.
FT VARIANT 314 314 R -> H (in CMD1R).
FT /FTId=VAR_012860.
FT VARIANT 333 333 A -> P (in CMH11).
FT /FTId=VAR_012861.
FT VARIANT 363 363 E -> G (in CMD1R).
FT /FTId=VAR_012862.
SQ SEQUENCE 377 AA; 42019 MW; E5C10FA19730CAD2 CRC64;
MCDDEETTAL VCDNGSGLVK AGFAGDDAPR AVFPSIVGRP RHQGVMVGMG QKDSYVGDEA
QSKRGILTLK YPIEHGIITN WDDMEKIWHH TFYNELRVAP EEHPTLLTEA PLNPKANREK
MTQIMFETFN VPAMYVAIQA VLSLYASGRT TGIVLDSGDG VTHNVPIYEG YALPHAIMRL
DLAGRDLTDY LMKILTERGY SFVTTAEREI VRDIKEKLCY VALDFENEMA TAASSSSLEK
SYELPDGQVI TIGNERFRCP ETLFQPSFIG MESAGIHETT YNSIMKCDID IRKDLYANNV
LSGGTTMYPG IADRMQKEIT ALAPSTMKIK IIAPPERKYS VWIGGSILAS LSTFQQMWIS
KQEYDEAGPS IVHRKCF
//
ID ACTC_HUMAN Reviewed; 377 AA.
AC P68032; P04270;
DT 20-MAR-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 20-MAR-1987, sequence version 1.
DT 22-JAN-2014, entry version 103.
DE RecName: Full=Actin, alpha cardiac muscle 1;
DE AltName: Full=Alpha-cardiac actin;
DE Flags: Precursor;
GN Name=ACTC1; Synonyms=ACTC;
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 [GENOMIC DNA].
RX PubMed=6310553; DOI=10.1073/pnas.79.19.5901;
RA Hamada H., Petrino M.G., Kakunaga T.;
RT "Molecular structure and evolutionary origin of human cardiac muscle
RT actin gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 79:5901-5905(1982).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=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 [4]
RP METHYLATION AT LYS-86, AND DEMETHYLATION BY ALKBH4.
RX PubMed=23673617; DOI=10.1038/ncomms2863;
RA Li M.M., Nilsen A., Shi Y., Fusser M., Ding Y.H., Fu Y., Liu B.,
RA Niu Y., Wu Y.S., Huang C.M., Olofsson M., Jin K.X., Lv Y., Xu X.Z.,
RA He C., Dong M.Q., Rendtlew Danielsen J.M., Klungland A., Yang Y.G.;
RT "ALKBH4-dependent demethylation of actin regulates actomyosin
RT dynamics.";
RL Nat. Commun. 4:1832-1832(2013).
RN [5]
RP VARIANTS CMD1R HIS-314 AND GLY-363.
RX PubMed=9563954; DOI=10.1126/science.280.5364.750;
RA Olson T.M., Michels V.V., Thibodeau S.N., Tai Y.-S., Keating M.T.;
RT "Actin mutations in dilated cardiomyopathy, a heritable form of heart
RT failure.";
RL Science 280:750-752(1998).
RN [6]
RP VARIANT CMH11 SER-297.
RX PubMed=10330430; DOI=10.1172/JCI6460;
RA Mogensen J., Klausen I.C., Pedersen A.K., Egeblad H., Bross P.,
RA Kruse T.A., Gregersen N., Hansen P.S., Baandrup U., Boerglum A.D.;
RT "Alpha-cardiac actin is a novel disease gene in familial hypertrophic
RT cardiomyopathy.";
RL J. Clin. Invest. 103:R39-R43(1999).
RN [7]
RP VARIANTS CMH11 LYS-101; ALA-166 AND PRO-333.
RX PubMed=10966831; DOI=10.1006/jmcc.2000.1204;
RA Olson T.M., Doan T.P., Kishimoto N.Y., Whitby F.G., Ackerman M.J.,
RA Fananapazir L.;
RT "Inherited and de novo mutations in the cardiac actin gene cause
RT hypertrophic cardiomyopathy.";
RL J. Mol. Cell. Cardiol. 32:1687-1694(2000).
RN [8]
RP VARIANTS CMH11 CYS-168 AND LEU-307.
RX PubMed=14729850; DOI=10.1136/jmg.2003.010447;
RA Mogensen J., Perrot A., Andersen P.S., Havndrup O., Klausen I.C.,
RA Christiansen M., Bross P., Egeblad H., Bundgaard H., Osterziel K.J.,
RA Haltern G., Lapp H., Reinecke P., Gregersen N., Borglum A.D.;
RT "Clinical and genetic characteristics of alpha cardiac actin gene
RT mutations in hypertrophic cardiomyopathy.";
RL J. Med. Genet. 41:E10-E10(2004).
RN [9]
RP VARIANT ASD5 VAL-125, AND CHARACTERIZATION OF VARIANT ASD5 VAL-125.
RX PubMed=17947298; DOI=10.1093/hmg/ddm302;
RA Matsson H., Eason J., Bookwalter C.S., Klar J., Gustavsson P.,
RA Sunnegardh J., Enell H., Jonzon A., Vikkula M., Gutierrez I.,
RA Granados-Riveron J., Pope M., Bu'Lock F., Cox J., Robinson T.E.,
RA Song F., Brook D.J., Marston S., Trybus K.M., Dahl N.;
RT "Alpha-cardiac actin mutations produce atrial septal defects.";
RL Hum. Mol. Genet. 17:256-265(2008).
RN [10]
RP VARIANTS CMH11 TYR-90 AND CYS-97.
RX PubMed=18403758; DOI=10.1056/NEJMoa075463;
RA Morita H., Rehm H.L., Menesses A., McDonough B., Roberts A.E.,
RA Kucherlapati R., Towbin J.A., Seidman J.G., Seidman C.E.;
RT "Shared genetic causes of cardiac hypertrophy in children and
RT adults.";
RL N. Engl. J. Med. 358:1899-1908(2008).
CC -!- FUNCTION: Actins are highly conserved proteins that are involved
CC in various types of cell motility and are ubiquitously expressed
CC in all eukaryotic cells.
CC -!- SUBUNIT: Polymerization of globular actin (G-actin) leads to a
CC structural filament (F-actin) in the form of a two-stranded helix.
CC Each actin can bind to 4 others.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton.
CC -!- PTM: Oxidation of Met-46 and Met-49 by MICALs (MICAL1, MICAL2 or
CC MICAL3) to form methionine sulfoxide promotes actin filament
CC depolymerization. MICAL1 and MICAL2 produce the (R)-S-oxide form.
CC The (R)-S-oxide form is reverted by MSRB1 and MSRB2, which promote
CC actin repolymerization (By similarity).
CC -!- PTM: Monomethylation at Lys-86 (K84me1) regulates actin-myosin
CC interaction and actomyosin-dependent processes. Demethylation by
CC ALKBH4 is required for maintaining actomyosin dynamics supporting
CC normal cleavage furrow ingression during cytokinesis and cell
CC migration.
CC -!- DISEASE: Cardiomyopathy, dilated 1R (CMD1R) [MIM:613424]: A
CC disorder characterized by ventricular dilation and impaired
CC systolic function, resulting in congestive heart failure and
CC arrhythmia. Patients are at risk of premature death. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Cardiomyopathy, familial hypertrophic 11 (CMH11)
CC [MIM:612098]: 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 Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Atrial septal defect 5 (ASD5) [MIM:612794]: A congenital
CC heart malformation characterized by incomplete closure of the wall
CC between the atria resulting in blood flow from the left to the
CC right atria. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- MISCELLANEOUS: In vertebrates 3 main groups of actin isoforms,
CC alpha, beta and gamma have been identified. The alpha actins are
CC found in muscle tissues and are a major constituent of the
CC contractile apparatus. The beta and gamma actins coexist in most
CC cell types as components of the cytoskeleton and as mediators of
CC internal cell motility.
CC -!- SIMILARITY: Belongs to the actin family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ACTC1";
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; J00073; AAB59619.1; -; Genomic_DNA.
DR EMBL; J00070; AAB59619.1; JOINED; Genomic_DNA.
DR EMBL; J00071; AAB59619.1; JOINED; Genomic_DNA.
DR EMBL; J00072; AAB59619.1; JOINED; Genomic_DNA.
DR EMBL; CR541795; CAG46594.1; -; mRNA.
DR EMBL; BC009978; AAH09978.1; -; mRNA.
DR PIR; A02998; ATHUC.
DR RefSeq; NP_005150.1; NM_005159.4.
DR UniGene; Hs.118127; -.
DR ProteinModelPortal; P68032; -.
DR SMR; P68032; 6-377.
DR IntAct; P68032; 13.
DR MINT; MINT-1425728; -.
DR STRING; 9606.ENSP00000290378; -.
DR PhosphoSite; P68032; -.
DR DMDM; 54036697; -.
DR REPRODUCTION-2DPAGE; P68032; -.
DR PaxDb; P68032; -.
DR PRIDE; P68032; -.
DR DNASU; 70; -.
DR Ensembl; ENST00000290378; ENSP00000290378; ENSG00000159251.
DR GeneID; 70; -.
DR KEGG; hsa:70; -.
DR UCSC; uc001ziu.1; human.
DR CTD; 70; -.
DR GeneCards; GC15M035080; -.
DR HGNC; HGNC:143; ACTC1.
DR HPA; CAB037330; -.
DR HPA; HPA041271; -.
DR MIM; 102540; gene.
DR MIM; 612098; phenotype.
DR MIM; 612794; phenotype.
DR MIM; 613424; phenotype.
DR neXtProt; NX_P68032; -.
DR Orphanet; 99103; Atrial septal defect, ostium secundum type.
DR Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR Orphanet; 54260; Left ventricular noncompaction.
DR PharmGKB; PA162375571; -.
DR eggNOG; COG5277; -.
DR HOGENOM; HOG000233340; -.
DR HOVERGEN; HBG003771; -.
DR InParanoid; P68032; -.
DR KO; K12314; -.
DR OMA; MGSANKT; -.
DR OrthoDB; EOG72RMZ1; -.
DR PhylomeDB; P68032; -.
DR Reactome; REACT_17044; Muscle contraction.
DR SignaLink; P68032; -.
DR GeneWiki; ACTC1; -.
DR GenomeRNAi; 70; -.
DR NextBio; 275; -.
DR PRO; PR:P68032; -.
DR ArrayExpress; P68032; -.
DR Bgee; P68032; -.
DR CleanEx; HS_ACTC1; -.
DR Genevestigator; P68032; -.
DR GO; GO:0042643; C:actomyosin, actin portion; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0031674; C:I band; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0016887; F:ATPase activity; IDA:UniProtKB.
DR GO; GO:0017022; F:myosin binding; IDA:BHF-UCL.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0060048; P:cardiac muscle contraction; IEA:Ensembl.
DR GO; GO:0055008; P:cardiac muscle tissue morphogenesis; ISS:UniProtKB.
DR GO; GO:0055003; P:cardiac myofibril assembly; ISS:UniProtKB.
DR GO; GO:0060047; P:heart contraction; IMP:UniProtKB.
DR GO; GO:0030049; P:muscle filament sliding; TAS:Reactome.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0030240; P:skeletal muscle thin filament assembly; ISS:UniProtKB.
DR InterPro; IPR004000; Actin-related.
DR InterPro; IPR020902; Actin/actin-like_CS.
DR InterPro; IPR004001; Actin_CS.
DR PANTHER; PTHR11937; PTHR11937; 1.
DR Pfam; PF00022; Actin; 1.
DR PRINTS; PR00190; ACTIN.
DR SMART; SM00268; ACTIN; 1.
DR PROSITE; PS00406; ACTINS_1; 1.
DR PROSITE; PS00432; ACTINS_2; 1.
DR PROSITE; PS01132; ACTINS_ACT_LIKE; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Atrial septal defect; Cardiomyopathy;
KW Complete proteome; Cytoplasm; Cytoskeleton; Disease mutation;
KW Methylation; Muscle protein; Nucleotide-binding; Oxidation;
KW Reference proteome.
FT PROPEP 1 2 Removed in mature form (By similarity).
FT /FTId=PRO_0000000812.
FT CHAIN 3 377 Actin, alpha cardiac muscle 1.
FT /FTId=PRO_0000000813.
FT MOD_RES 3 3 N-acetylaspartate (By similarity).
FT MOD_RES 46 46 Methionine (R)-sulfoxide (By similarity).
FT MOD_RES 49 49 Methionine (R)-sulfoxide (By similarity).
FT MOD_RES 75 75 Tele-methylhistidine (By similarity).
FT MOD_RES 86 86 N6-methyllysine.
FT VARIANT 90 90 H -> Y (in CMH11).
FT /FTId=VAR_045924.
FT VARIANT 97 97 R -> C (in CMH11).
FT /FTId=VAR_045925.
FT VARIANT 101 101 E -> K (in CMH11).
FT /FTId=VAR_012857.
FT VARIANT 125 125 M -> V (in ASD5; reduced affinity for
FT myosin; normal actin filament
FT polymerization ability; normal actomyosin
FT motor function).
FT /FTId=VAR_046502.
FT VARIANT 166 166 P -> A (in CMH11).
FT /FTId=VAR_012858.
FT VARIANT 168 168 Y -> C (in CMH11).
FT /FTId=VAR_046503.
FT VARIANT 297 297 A -> S (in CMH11).
FT /FTId=VAR_012859.
FT VARIANT 307 307 M -> L (in CMH11).
FT /FTId=VAR_046504.
FT VARIANT 314 314 R -> H (in CMD1R).
FT /FTId=VAR_012860.
FT VARIANT 333 333 A -> P (in CMH11).
FT /FTId=VAR_012861.
FT VARIANT 363 363 E -> G (in CMD1R).
FT /FTId=VAR_012862.
SQ SEQUENCE 377 AA; 42019 MW; E5C10FA19730CAD2 CRC64;
MCDDEETTAL VCDNGSGLVK AGFAGDDAPR AVFPSIVGRP RHQGVMVGMG QKDSYVGDEA
QSKRGILTLK YPIEHGIITN WDDMEKIWHH TFYNELRVAP EEHPTLLTEA PLNPKANREK
MTQIMFETFN VPAMYVAIQA VLSLYASGRT TGIVLDSGDG VTHNVPIYEG YALPHAIMRL
DLAGRDLTDY LMKILTERGY SFVTTAEREI VRDIKEKLCY VALDFENEMA TAASSSSLEK
SYELPDGQVI TIGNERFRCP ETLFQPSFIG MESAGIHETT YNSIMKCDID IRKDLYANNV
LSGGTTMYPG IADRMQKEIT ALAPSTMKIK IIAPPERKYS VWIGGSILAS LSTFQQMWIS
KQEYDEAGPS IVHRKCF
//
MIM
102540
*RECORD*
*FIELD* NO
102540
*FIELD* TI
*102540 ACTIN, ALPHA, CARDIAC MUSCLE; ACTC1
;;ACTC;;
SMOOTH MUSCLE ACTIN;;
ACTIN, ALPHA
read more*FIELD* TX
CLONING
Because actin is a highly conserved protein, Engel et al. (1981) could
use cloned actin genes from Drosophila and from chicken to isolate 12
actin gene fragments from a human DNA library. Restriction endonuclease
studies of each indicated that they are not allelic and are from
nonoverlapping regions of the genome. In all, 25 to 30 EcoRI fragments
homologous to actin genes were found in the human genome and no
restriction site polymorphism was found indicating evolutionary
conservatism.
Humphries et al. (1981) used probes from the mouse to detect actin genes
in human DNA and concluded that there are about 20 actin genes in the
human genome. Three lines of evidence supported this number: the rate of
hybridization of the mouse probe with human DNA; the fact that the probe
hybridizes to 17-20 bands in Southern blots of restriction enzyme
digests of total human DNA; restriction enzyme mapping of individual
human actin genes indicating at least 9 different genes, judged on
probability grounds to have been picked from a pool of at least 20.
Hamada et al. (1982) isolated and characterized the human cardiac actin
gene. The cardiac and skeletal actin genes showed close similarity,
suggesting a relatively recent derivation from a common ancestral gene.
Nucleotide sequences of all exon/intron boundaries agreed with the GT/AG
rule (GT at the 5-prime and AG at the 3-prime termini of each intron).
Gunning et al. (1984) noted that the cardiac actin gene and the skeletal
actin gene (102610) on chromosome 1 are coexpressed in both skeletal and
heart muscle.
MAPPING
Using a cDNA fragment from an exon of the human cardiac actin gene in
somatic hybrid cell studies, Shows et al. (1984) showed that the gene is
coded by the segment 15q11-qter. Crosby et al. (1989) showed that in the
mouse the cardiac actin gene (Actc-1) is not on chromosome 17 as
previously reported (Czosnek et al., 1983) but is located on chromosome
2. It is closely linked to beta-2-microglobulin as indicated by mapping
studies using restriction fragment variants in recombinant inbred
strains. Using a highly polymorphic CA repeat microsatellite within
intron 4 of the ACTC gene, Kramer et al. (1992) did family linkage
studies with multiple markers on 15q, thus permitting the gene to be
placed on the chromosome linkage map. They demonstrated that it lies
about 0.06 cM proximal to D15S49, which is about 0.05 cM proximal to
D15S25, which in turn is about 0.07 cM proximal to D15S1; D15S1 is
tightly linked to the Marfan syndrome and to fibrillin. Thus ACTC may be
about 0.18 cM proximal to the fibrillin locus and no more distal than
15q21.1.
By fluorescence in situ hybridization, Ueyama et al. (1995) assigned the
ACTC1 gene to chromosome 15q14.
GENE FUNCTION
Actin has been identified in many kinds of cells including muscle, where
it is a major constituent of the thin filament, and platelets. Muscle
actins from sources as diverse as rabbits and fish are very similar in
amino acid sequence. Elzinga et al. (1976) examined whether actin in
different tissues of the same organism are products of the same gene.
They found that human platelet and human cardiac actins differ by one
amino acid, viz., threonine and valine, respectively, at position 129.
Thus they must be determined by different genes. Actins can be separated
by isoelectric focusing into 3 main groups which show more than 90%
homology of amino acid sequence. Firtel (1981) referred to the actin of
smooth muscle, the most acidic form, as alpha type and the 2 cytoplasmic
forms as beta and gamma. Beta and gamma actins are involved in the
cytoskeleton and in internal cell mobility phenomena.
The actins constitute multiple gene families. There is only a 4% amino
acid difference in the actins of Physarum and mammals. In mammals, 4
different muscle actins have been sequenced: from fast muscle, heart,
aorta, and stomach. These vary only by 4 to 6 amino acids from each
other, and by about 25 amino acids from the beta and gamma actins. Thus,
from the protein data, at least 6 actin genes would be expected in
mammals. Recombinant DNA probes for both actin and myosin of the mouse
have been made (Weydert et al., 1981).
Buckingham et al. (1986) provided a summary of the actin and myosin
multigene families in mouse and man. Certain inbred mouse lines, e.g.,
BALB/c, have a mutant cardiac actin locus (Garner et al., 1986). The
first 3 coding exons and promoter region of the gene are present as a
duplication immediately upstream from the cardiac actin gene. The
upstream promoter is active, and partial gene transcripts are generated
which are correctly spliced for the first 3 coding exons but which
terminate at cryptic sites in the region between the duplication and the
gene. Transcriptional activity at the upstream promoter interferes with
the downstream promoter of the bona fide cardiac actin gene, leading to
a 5- to 6-fold reduction in cardiac actin mRNA in the hearts of BALB/c
mice. In this situation there is an accumulation of skeletal actin gene
transcripts in the adult hearts of these mice, which partially
compensates for the reduction in cardiac actin transcripts. BALB/c mice
have a normal life span and their hearts do not undergo hypertrophy.
Apparently, cardiac and skeletal actins, which differ only by 4 out of
375 amino acids, are to some extent interchangeable. Schwartz et al.
(1986) found that under conditions of aortic stenosis leading to cardiac
overload and cardiac hypertrophy, skeletal actin gene transcripts are
found in adult rodent hearts in addition to the cardiac actin gene
products normally present.
Matsson et al. (2008) performed morpholino knockdown of the Actc1 gene
in chick embryos and found significant association with delayed looping
and reduced atrial septa, supporting a developmental role for the
protein.
MOLECULAR GENETICS
Litt and Luty (1989) used PCR to amplify a microsatellite hypervariable
repeat in the human cardiac actin gene. They detected 12 different
allelic fragments in 37 unrelated individuals, of whom 32 were
heterozygous.
(Weber and May (1989) also found that (GT)n repeats within human loci
are highly polymorphic.) In vertebrates, 6 actin isoforms are known: 4
muscle types (skeletal, cardiac, and 2 smooth muscle types) and 2
nonmuscle types (cytoplasmic actins).
- Dilated Cardiomyopathy 1R
To test the hypothesis that actin dysfunction leads to heart failure,
Olson et al. (1998) examined patients with hereditary idiopathic dilated
cardiomyopathy (see 115200) for mutations in the cardiac ACTC gene.
Missense mutations in ACTC (102540.0001 and 102540.0002) that
cosegregated with a form of dilated cardiomyopathy, here designated
CMD1R (613424), were identified in 2 unrelated families, respectively.
Both mutations affected universally conserved amino acids in domains of
actin that attached to Z bands and intercalated discs. Coupled with
previous data showing that dystrophin mutations also cause dilated
cardiomyopathy, these results raised the possibility that defective
transmission of force in cardiac myocytes is a mechanism underlying
heart failure.
To determine how frequently mutations in the ACTC gene are responsible
for dilated cardiomyopathy, Takai et al. (1999) studied 136 Japanese
cases of this disorder. Although several polymorphisms were found, no
disease-causing changes were identified, leading Takai et al. (1999) to
conclude that mutation in the ACTC gene is a rare cause of dilated
cardiomyopathy, at least in Japanese patients.
Mayosi et al. (1999) studied 57 South African patients with dilated
cardiomyopathy, 56% of whom were of black African origin. No mutation
predicted to produce an alteration in protein was identified in either
the skeletal or cardiac actin genes in any patient.
- Hypertrophic Cardiomyopathy 11
In a large 3-generation family with hypertrophic cardiomyopathy (CMH11;
612098), Mogensen et al. (1999) identified heterozygosity for a missense
mutation in the ACTC1 gene (A295S; 102540.0003) that was located near 2
missense mutations previously identified as causing an inherited form of
dilated cardiomyopathy (CMD1R). The authors stated that ACTC1 was the
first sarcomeric gene described in which mutations are responsible for 2
different cardiomyopathies, and hypothesized that ACTC1 mutations
affecting sarcomere contraction lead to HCM and that mutations affecting
force transmission from the sarcomere to the surrounding syncytium lead
to dilated cardiomyopathy.
Olson et al. (2000) screened the ACTC1 gene in 368 unrelated patients
with sporadic or familial CMH and identified 3 different heterozygous
mutations in 2 sporadic patients with apical CMH (102540.0007 and
102540.0008, respectively) and in a 4-generation family segregating
autosomal dominant CMH (E101K; 102540.0009). None of the mutations was
detected in 150 unrelated controls, and each involved a highly conserved
residue in ACTC1. The authors noted that these and previously identified
CMH-related ACTC1 mutations are likely to affect actin-myosin
interaction and force generation; in contrast, CMD-related ACTC1
mutations (e.g., R312H and E361G) are not located in domains interacting
with the myosin head, but rather occur in a region of the actin monomer
that forms the immobilized end of the actin filament. Olson et al.
(2000) concluded that mutations in ACTC1 can cause either CMH or CMD,
depending on the functional domain of actin that is affected.
In affected members of 2 families segregating autosomal dominant apical
CMH over 3 generations, Arad et al. (2005) identified heterozygosity for
the E101K mutation in the ACTC1 gene.
Monserrat et al. (2007) screened 247 probands with CMH, CMD, or left
ventricular noncompaction (see LVNC4, 613424) for the E101K mutation,
and identified the mutation in 4 probands with CMH, 2 of whom were
previously studied by Arad et al. (2005), and in 1 proband with LVNC. Of
46 family members with CMH, 23 fulfilled criteria for LVNC, 22 were
diagnosed with apical CMH, and 3 had been diagnosed with restrictive
cardiomyopathy. Septal defects were identified in 9 mutation carriers
from 4 families (8 atrial defects and 1 ventricular), and were absent in
relatives without the mutation. Monserrat et al. (2007) concluded that
LVNC and CMH may appear as overlapping entities, and that E101K should
be considered in the genetic diagnosis of LVNC, apical CMH, and septal
defects.
In 2 unrelated children with idiopathic cardiac hypertrophy and presumed
sporadic cardiomyopathy, Morita et al. (2008) identified 2 different
missense mutations in the ACTC1 gene (see, e.g., 102540.0004); 1 of the
children also carried a missense mutation in the MYH7 gene (160760),
which is known to cause CMH1 (192600). The parents were not studied.
- Left Ventricular Noncompaction 4
Klaassen et al. (2008) analyzed 6 sarcomere protein genes in 63
unrelated adult probands with left ventricular noncompaction (see LVNC4;
613424) and no other congenital heart anomalies and identified the E101K
mutation in the ACTC1 gene in 2 probands.
- Atrial Septal Defect 5
Matsson et al. (2008) analyzed the ACTC1 gene in 2 large Swedish
families segregating autosomal dominant secundum atrial septal defect
(ASD5; 612794) and identified heterozygosity for a mutation (M123V;
102540.0005) in the 20 available affected individuals. The authors
studied 408 additional individuals referred for sporadic congenital
heart disease and identified a 17-bp deletion (102540.0006) in the ACTC1
gene in a 10-year-old girl with secundum ASD.
*FIELD* AV
.0001
CARDIOMYOPATHY, DILATED, 1R
ACTC1, ARG312HIS
In a 36-year-old mother and 2 daughters, aged 5 and 2 years, of German
ancestry who had dilated cardiomyopathy (CMD1R; 613424), Olson et al.
(1998) found a G-to-A substitution in codon 312 in exon 5 of the ACTC
gene, resulting in an arg312-to-his (R312H) amino acid substitution. A
15-year-old son likewise had inherited the mutation but had not
developed dilated cardiomyopathy.
.0002
CARDIOMYOPATHY, DILATED, 1R
ACTC1, GLU361GLY
In a family of Swedish Norwegian ancestry, Olson et al. (1998) found
that a father and son, aged 41 and 14 years, respectively, with dilated
cardiomyopathy-1R (613424) carried a GAG (glu)-to-GGG (gly) mutation in
codon 361 in exon 6 of the ACTC gene. In addition, a 34-year-old woman
with a dilated heart and a 9-year-old with borderline heart size also
had inherited the mutation.
.0003
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11
ACTC1, ALA295SER
In a 3-generation family with autosomal dominant hypertrophic
cardiomyopathy (612098), Mogensen et al. (1999) identified a 253G-T
transversion in exon 5 of the ACTC gene resulting in an ala295-to-ser
substitution. The ala at position 295 is conserved in 19 different
species. The expression of the actin mutation in this family gave the
impression of a highly penetrant disease with diverse phenotypes and
variable age of onset. Only 1 individual of 13 family members carrying
the mutant allele was nonpenetrant, and morbidity was low, as only 3 of
the 13 carrying the mutant allele had symptoms of the disease.
.0004
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11
ACTC1, HIS90TYR
In a child with idiopathic cardiac hypertrophy and presumed sporadic
cardiomyopathy (612098) who was negative for mutation in 9 of the known
CMH genes, Morita et al. (2008) identified a heterozygous C-to-T
transition in the ACTC1 gene resulting in a his90-to-tyr (H90Y)
substitution. The parents were not studied. The mutation was not found
in unrelated individuals matched by ancestral origin or in more than
1,000 control chromosomes.
.0005
ATRIAL SEPTAL DEFECT 5
ACTC1, MET123VAL
In 20 affected individuals from 2 Swedish families segregating autosomal
dominant atrial septal defect (ASD5; 612794), Matsson et al. (2008)
identified heterozygosity for a 373A-G transition in exon 2 of the ACTC1
gene, predicted to result in a met123-to-val (M123V) substitution.
Functional analysis of the M123V-mutant protein showed a reduced
affinity for myosin, but retention of actin filament polymerization and
actomyosin motor properties. The mutation was not found in 580 control
samples.
.0006
ATRIAL SEPTAL DEFECT 5
ACTC1, 17-BP DEL, NT251
In a 10-year-old girl with a secundum atrial septal defect (ASD5;
612794), Matsson et al. (2008) identified heterozygosity for a 17-bp
deletion beginning at nucleotide 251 in exon 2 of the ACTC1 gene,
predicted to result in a severely truncated protein of 86 amino acids in
length. The mutation was also identified in her clinically unaffected
43-year-old father, who was found to have an abnormal echocardiogram
with a posteriorly deviated interventricular septum, believed to be
associated with a spontaneously closed perimembranous ventricular septal
defect, causing aortic valve regurgitation. The deletion was not found
in 580 control samples.
.0007
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11
ACTC1, ALA331PRO
In a 21-year-old man with hypertrophic cardiomyopathy (CMH11; 612098),
Olson et al. (2000) identified heterozygosity for a G-C transversion in
exon 6 of the ACTC1 gene, resulting in an ala331-to-pro (A331P)
substitution at a highly conserved residue. The patient presented at 8
years of age with 2 near-syncopal episodes and was diagnosed with
idiopathic CMH. At 10 years of age, he was resuscitated from ventricular
fibrillation that occurred while running, and a defibrillator was
placed. Cardiac evaluation revealed hypertrophy of the septum and left
ventricular apex. His unaffected parents did not carry the mutation, nor
was it found in 150 unrelated controls.
.0008
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11
ACTC1, PRO164ALA
In a 12-year-old boy with hypertrophic cardiomyopathy-11 (612098), Olson
et al. (2000) identified heterozygosity for a C-G transversion in exon 2
of the ACTC1 gene, resulting in a pro164-to-ala (P164A) substitution at
a highly conserved residue. The patient was diagnosed with CMH at 17
months of age due to syncopal episodes. He later had occasional episodes
of chest pain, dyspnea, and near-syncope, and underwent insertion of a
pacemaker. Cardiac evaluation revealed hypertrophy of the septum and
left ventricular apex. His unaffected parents did not carry the
mutation, nor was it found in 150 unrelated controls.
.0009
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11
LEFT VENTRICULAR NONCOMPACTION 4, INCLUDED
ACTC1, GLU101LYS
Using a new numbering system, Arad et al. (2005) designated this
mutation GLU101LYS (E101K).
In 7 affected members of a 4-generation family segregating autosomal
dominant hypertrophic cardiomyopathy (CMH11; 612098), Olson et al.
(2000) identified heterozygosity for a G-A transition in exon 2 of the
ACTC1 gene, resulting in a glu99-to-lys (GLU99LYS) substitution at a
highly conserved residue. Apical left ventricular hypertrophy was
present in 5 cases and a trabeculated apex in 2 cases; 2 individuals
also had marked hypertrophy of the interventricular septum without left
ventricular outflow obstruction, and 1 had an atrial septal defect.
In affected members of 2 families segregating autosomal dominant apical
CMH over 3 generations, Arad et al. (2005) identified heterozygosity for
the E101K mutation in the ACTC1 gene. A shared haplotype was also
identified, providing odds greater than 100:1 that E101K represents a
founding mutation in the 2 families; however, haplotype data indicated
that E101K arose independently in the family reported by Olson et al.
(2000). Of 18 mutation-positive individuals studied by Arad et al.
(2005), 2 individuals, ages 10 and 29 years, had no clinical evidence of
cardiomyopathy. Isolated apical hypertrophy was found in 5 individuals;
11 others also had mild thickening of the basal segments and/or
involvement of the midventricular segment, and 2 also had trabeculation
of the apex. Right ventricular endomyocardial biopsy in 1 patient
revealed myocyte hypertrophy and disarray with extensive replacement
fibrosis that was more marked than that typically seen in CMH associated
with other morphologic patterns of hypertrophy.
Monserrat et al. (2007) screened 247 probands with CMH, dilated
cardiomyopathy (CMD), or left ventricular noncompaction (see LVNC4,
613424) for the E101K mutation, and identified the mutation in 4
probands with CMH and 1 with LVNC. The 5 mutation-positive families, 2
of which were previously studied by Arad et al. (2005), were all from
the same local area in Galicia, Spain, and shared the same 88-bp allele
of the intragenic ACTC1 microsatellite marker that cosegregated with
disease in the families, suggesting a likely founder effect. Of 46
family members with CMH, 23 fulfilled criteria for LVNC, 22 were
diagnosed with apical CMH, and 3 had been diagnosed with restrictive
cardiomyopathy. Septal defects were identified in 9 mutation carriers
from 4 families (8 atrial defects and 1 ventricular), and were absent in
relatives without the mutation. The E101K mutation was not found in 48
unaffected family members. Monserrat et al. (2007) concluded that LVNC
and CMH may appear as overlapping entities, and that E101K should be
considered in the genetic diagnosis of LVNC, apical CMH, and septal
defects.
In a 15-year-old girl and an unrelated 38-year-old woman with LVNC,
Klaassen et al. (2008) identified heterozygosity for the E101K mutation
in the ACTC1 gene. Both had inherited the mutation from their affected
fathers; haplotype analysis excluded a common ancestor. All 4 patients
had noncompaction of the apex and midventricular wall and no other
congenital cardiac anomalies.
*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. Buckingham, M.; Alonso, S.; Barton, P.; Cohen, A.; Daubas, P.;
Garner, I.; Robert, B.; Weydert, A.: Actin and myosin multigene families:
their expression during the formation and maturation of striated muscle. Am.
J. Med. Genet. 25: 623-634, 1986.
3. Crosby, J. L.; Phillips, S. J.; Nadeau, J. H.: The cardiac actin
locus (Actc-1) is not on mouse chromosome 17 but is linked to beta-2-microglobulin
on chromosome 2. Genomics 5: 19-23, 1989.
4. Czosnek, H.; Nudel, U.; Mayer, Y.; Barker, P. E.; Pravtcheva, D.
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actin, the skeletal muscle actin and the cytoplasmic beta-actin are
located on three different mouse chromosomes. EMBO J. 2: 1977-1979,
1983.
5. Elzinga, M.; Maron, B. J.; Adelstein, R. S.: Human heart and platelet
actins are products of different genes. Science 191: 94-95, 1976.
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of human actin genes. Proc. Nat. Acad. Sci. 78: 4674-4678, 1981.
7. Firtel, R. A.: Multigene families encoding actin and tubulin. Cell 24:
6-7, 1981.
8. Garner, I.; Minty, A. J.; Alonso, S.; Barton, P. J.; Buckingham,
M. E.: A 5-prime duplication of the alpha-cardiac actin gene in BALB/c
mice is associated with abnormal levels of alpha-cardiac and alpha-skeletal
actin mRNAs in adult cardiac tissue. EMBO J. 5: 2559-2567, 1986.
9. Gunning, P.; Ponte, P.; Kedes, L.; Eddy, R.; Shows, T.: Chromosomal
location of the co-expressed human skeletal and cardiac actin genes. Proc.
Nat. Acad. Sci. 81: 1813-1817, 1984.
10. Hamada, H.; Petrino, M. G.; Kakunaga, T.: Molecular structure
and evolutionary origin of human cardiac muscle actin gene. Proc.
Nat. Acad. Sci. 79: 5901-5905, 1982.
11. Humphries, S. E.; Whittall, R.; Minty, A.; Buckingham, M.; Williamson,
R.: There are approximately 20 actin genes in the human genome. Nucleic
Acids Res. 9: 4895-4908, 1981.
12. Klaassen, S.; Probst, S.; Oechslin, E.; Gerull, B.; Krings, G.;
Schuler, P.; Greutmann, M.; Hurlimann, D.; Yegibasi, M.; Pons, L.;
Gramlich, M.; Drenckhahn, J.-D.; Heuser, A.; Berger, F.; Jenni, R.;
Thierfelder, L.: Mutations in sarcomere protein genes in left ventricular
noncompaction. Circulation 117: 2893-2901, 2008.
13. Kramer, P. L.; Luty, J. A.; Litt, M.: Regional localization of
the gene for cardiac muscle actin (ACTC) on chromosome 15q. Genomics 13:
904-905, 1992.
14. Litt, M.; Luty, J. A.: A hypervariable microsatellite revealed
by in vitro amplification of a dinucleotide repeat within the cardiac
muscle actin gene. Am. J. Hum. Genet. 44: 397-401, 1989.
15. Matsson, H.; Eason, J.; Bookwalter, C. S.; Klar, J.; Gustavsson,
P.; Sunnegardh, J.; Enell, H.; Jonzon, A.; Vikkula, M.; Gutierrez,
I.; Granados-Riveron, J.; Pope, M.; Bu'Lock, F.; Cox, J.; Robinson,
T. E.; Song, F.; Brook, D. J.; Marston, S.; Trybus, K. M.; Dahl, N.
: Alpha-cardiac actin mutations produce atrial septal defects. Hum.
Molec. Genet. 17: 256-265, 2008.
16. Mayosi, B. M.; Khogali, S. S.; Zhang, B.; Watkins, H.: Cardiac
and skeletal actin gene mutations are not a common cause of dilated
cardiomyopathy. J. Med. Genet. 36: 796-797, 1999.
17. Mogensen, J.; Klausen, I. C.; Pedersen, A. K.; Egeblad, H.; Bross,
P.; Kruse, T. A.; Gregersen, N.; Hansen, P. S.; Baandrup, U.; Borglum,
A. D.: Alpha-cardiac actin is a novel disease gene in familial hypertrophic
cardiomyopathy. J. Clin. Invest. 103: R39-R43, 1999.
18. Monserrat, L.; Hermida-Prieto, M.; Fernandez, X.; Rodriguez, I.;
Dumont, C.; Cazon, L.; Cuesta, M. G.; Gonzalez-Juanatey, C.; Peteiro,
J.; Alvarez, N.; Penas-Lado, M.; Castro-Beiras, A.: Mutation in the
alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy,
left ventricular non-compaction, and septal defects. Europ. Heart
J. 28: 1953-1961, 2007.
19. Morita, H.; Rehm, H. L.; Menesses, A.; McDonough, B.; Roberts,
A. E.; Kucherlapati, R.; Towbin, J. A.; Seidman, J. G.; Seidman, C.
E.: Shared genetic causes of cardiac hypertrophy in children and
adults. New Eng. J. Med. 358: 1899-1908, 2008.
20. Olson, T. M.; Doan, T. P.; Kishimoto, N. Y.; Whitby, F. G.; Ackerman,
M. J.; Fananapazir, L.: Inherited and de novo mutations in the cardiac
actin gene cause hypertrophic cardiomyopathy. J. Molec. Cell Cardiol. 32:
1687-1694, 2000.
21. Olson, T. M.; Michels, V. V.; Thibodeau, S. N.; Tai, Y.-S.; Keating,
M. T.: Actin mutations in dilated cardiomyopathy, a heritable form
of heart failure. Science 280: 750-752, 1998.
22. Schwartz, K.; de la Bastie, D.; Bouveret, P.; Oliviero, P.; Alonso,
S.; Buckingham, M.: Alpha-skeletal muscle actin mRNAs accumulate
in hypertrophied adult rat hearts. Circulation Res. 59: 551-555,
1986.
23. Shows, T.; Eddy, R. L.; Haley, L.; Byers, M.; Henry, M.; Gunning,
P.; Ponte, P.; Kedes, L.: The coexpressed genes for human alpha (ACTA)
and cardiac actin (ACTC) are on chromosomes 1 and 15, respectively.
(Abstract) Cytogenet. Cell Genet. 37: 583 only, 1984.
24. Takai, E.; Akita, H.; Shiga, N.; Kanazawa, K.; Yamada, S.; Terashima,
M.; Matsuda, Y.; Iwai, C.; Kawai, K.; Yokota, Y.; Yokoyama, M.: Mutational
analysis of the cardiac actin gene in familial and sporadic dilated
cardiomyopathy. Am. J. Med. Genet. 86: 325-327, 1999.
25. Ueyama, H.; Inazawa, J.; Ariyama, T.; Nishino, H.; Ochiai, Y.;
Ohkubo, I.; Miwa, T.: Reexamination of chromosomal loci of human
muscle actin genes by fluorescence in situ hybridization. Jpn. J.
Hum. Genet. 40: 145-148, 1995.
26. Weber, J. L.; May, P. E.: Abundant class of human DNA polymorphisms
which can be typed using the polymerase chain reaction. Am. J. Hum.
Genet. 44: 388-396, 1989.
27. Weydert, A.; Robert, B.; Alonso, S.; Caravatti, M.; Cohen, A.;
Daubas, P.; Minty, A.; Buckingham, M.: Multigene families of contractile
proteins: the actins and myosins. (Abstract) Sixth Int. Cong. Hum.
Genet., Jerusalem 39 only, 1981.
*FIELD* CN
Marla J. F. O'Neill - updated: 06/07/2010
Marla J. F. O'Neill - updated: 5/4/2009
Marla J. F. O'Neill - updated: 6/4/2008
Ada Hamosh - updated: 3/17/2000
Michael J. Wright - updated: 2/4/2000
Victor A. McKusick - updated: 10/28/1999
Victor A. McKusick - updated: 4/28/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 06/07/2010
wwang: 5/20/2009
terry: 5/4/2009
carol: 6/5/2008
carol: 6/4/2008
terry: 6/4/2008
carol: 11/20/2007
carol: 9/10/2007
wwang: 2/23/2006
alopez: 3/22/2000
terry: 3/17/2000
alopez: 2/4/2000
carol: 11/4/1999
terry: 10/28/1999
carol: 3/22/1999
alopez: 4/28/1998
terry: 4/28/1998
carol: 6/20/1997
mark: 11/27/1996
terry: 6/16/1995
carol: 11/18/1994
carol: 10/13/1993
carol: 8/25/1992
carol: 6/29/1992
carol: 3/20/1992
*RECORD*
*FIELD* NO
102540
*FIELD* TI
*102540 ACTIN, ALPHA, CARDIAC MUSCLE; ACTC1
;;ACTC;;
SMOOTH MUSCLE ACTIN;;
ACTIN, ALPHA
read more*FIELD* TX
CLONING
Because actin is a highly conserved protein, Engel et al. (1981) could
use cloned actin genes from Drosophila and from chicken to isolate 12
actin gene fragments from a human DNA library. Restriction endonuclease
studies of each indicated that they are not allelic and are from
nonoverlapping regions of the genome. In all, 25 to 30 EcoRI fragments
homologous to actin genes were found in the human genome and no
restriction site polymorphism was found indicating evolutionary
conservatism.
Humphries et al. (1981) used probes from the mouse to detect actin genes
in human DNA and concluded that there are about 20 actin genes in the
human genome. Three lines of evidence supported this number: the rate of
hybridization of the mouse probe with human DNA; the fact that the probe
hybridizes to 17-20 bands in Southern blots of restriction enzyme
digests of total human DNA; restriction enzyme mapping of individual
human actin genes indicating at least 9 different genes, judged on
probability grounds to have been picked from a pool of at least 20.
Hamada et al. (1982) isolated and characterized the human cardiac actin
gene. The cardiac and skeletal actin genes showed close similarity,
suggesting a relatively recent derivation from a common ancestral gene.
Nucleotide sequences of all exon/intron boundaries agreed with the GT/AG
rule (GT at the 5-prime and AG at the 3-prime termini of each intron).
Gunning et al. (1984) noted that the cardiac actin gene and the skeletal
actin gene (102610) on chromosome 1 are coexpressed in both skeletal and
heart muscle.
MAPPING
Using a cDNA fragment from an exon of the human cardiac actin gene in
somatic hybrid cell studies, Shows et al. (1984) showed that the gene is
coded by the segment 15q11-qter. Crosby et al. (1989) showed that in the
mouse the cardiac actin gene (Actc-1) is not on chromosome 17 as
previously reported (Czosnek et al., 1983) but is located on chromosome
2. It is closely linked to beta-2-microglobulin as indicated by mapping
studies using restriction fragment variants in recombinant inbred
strains. Using a highly polymorphic CA repeat microsatellite within
intron 4 of the ACTC gene, Kramer et al. (1992) did family linkage
studies with multiple markers on 15q, thus permitting the gene to be
placed on the chromosome linkage map. They demonstrated that it lies
about 0.06 cM proximal to D15S49, which is about 0.05 cM proximal to
D15S25, which in turn is about 0.07 cM proximal to D15S1; D15S1 is
tightly linked to the Marfan syndrome and to fibrillin. Thus ACTC may be
about 0.18 cM proximal to the fibrillin locus and no more distal than
15q21.1.
By fluorescence in situ hybridization, Ueyama et al. (1995) assigned the
ACTC1 gene to chromosome 15q14.
GENE FUNCTION
Actin has been identified in many kinds of cells including muscle, where
it is a major constituent of the thin filament, and platelets. Muscle
actins from sources as diverse as rabbits and fish are very similar in
amino acid sequence. Elzinga et al. (1976) examined whether actin in
different tissues of the same organism are products of the same gene.
They found that human platelet and human cardiac actins differ by one
amino acid, viz., threonine and valine, respectively, at position 129.
Thus they must be determined by different genes. Actins can be separated
by isoelectric focusing into 3 main groups which show more than 90%
homology of amino acid sequence. Firtel (1981) referred to the actin of
smooth muscle, the most acidic form, as alpha type and the 2 cytoplasmic
forms as beta and gamma. Beta and gamma actins are involved in the
cytoskeleton and in internal cell mobility phenomena.
The actins constitute multiple gene families. There is only a 4% amino
acid difference in the actins of Physarum and mammals. In mammals, 4
different muscle actins have been sequenced: from fast muscle, heart,
aorta, and stomach. These vary only by 4 to 6 amino acids from each
other, and by about 25 amino acids from the beta and gamma actins. Thus,
from the protein data, at least 6 actin genes would be expected in
mammals. Recombinant DNA probes for both actin and myosin of the mouse
have been made (Weydert et al., 1981).
Buckingham et al. (1986) provided a summary of the actin and myosin
multigene families in mouse and man. Certain inbred mouse lines, e.g.,
BALB/c, have a mutant cardiac actin locus (Garner et al., 1986). The
first 3 coding exons and promoter region of the gene are present as a
duplication immediately upstream from the cardiac actin gene. The
upstream promoter is active, and partial gene transcripts are generated
which are correctly spliced for the first 3 coding exons but which
terminate at cryptic sites in the region between the duplication and the
gene. Transcriptional activity at the upstream promoter interferes with
the downstream promoter of the bona fide cardiac actin gene, leading to
a 5- to 6-fold reduction in cardiac actin mRNA in the hearts of BALB/c
mice. In this situation there is an accumulation of skeletal actin gene
transcripts in the adult hearts of these mice, which partially
compensates for the reduction in cardiac actin transcripts. BALB/c mice
have a normal life span and their hearts do not undergo hypertrophy.
Apparently, cardiac and skeletal actins, which differ only by 4 out of
375 amino acids, are to some extent interchangeable. Schwartz et al.
(1986) found that under conditions of aortic stenosis leading to cardiac
overload and cardiac hypertrophy, skeletal actin gene transcripts are
found in adult rodent hearts in addition to the cardiac actin gene
products normally present.
Matsson et al. (2008) performed morpholino knockdown of the Actc1 gene
in chick embryos and found significant association with delayed looping
and reduced atrial septa, supporting a developmental role for the
protein.
MOLECULAR GENETICS
Litt and Luty (1989) used PCR to amplify a microsatellite hypervariable
repeat in the human cardiac actin gene. They detected 12 different
allelic fragments in 37 unrelated individuals, of whom 32 were
heterozygous.
(Weber and May (1989) also found that (GT)n repeats within human loci
are highly polymorphic.) In vertebrates, 6 actin isoforms are known: 4
muscle types (skeletal, cardiac, and 2 smooth muscle types) and 2
nonmuscle types (cytoplasmic actins).
- Dilated Cardiomyopathy 1R
To test the hypothesis that actin dysfunction leads to heart failure,
Olson et al. (1998) examined patients with hereditary idiopathic dilated
cardiomyopathy (see 115200) for mutations in the cardiac ACTC gene.
Missense mutations in ACTC (102540.0001 and 102540.0002) that
cosegregated with a form of dilated cardiomyopathy, here designated
CMD1R (613424), were identified in 2 unrelated families, respectively.
Both mutations affected universally conserved amino acids in domains of
actin that attached to Z bands and intercalated discs. Coupled with
previous data showing that dystrophin mutations also cause dilated
cardiomyopathy, these results raised the possibility that defective
transmission of force in cardiac myocytes is a mechanism underlying
heart failure.
To determine how frequently mutations in the ACTC gene are responsible
for dilated cardiomyopathy, Takai et al. (1999) studied 136 Japanese
cases of this disorder. Although several polymorphisms were found, no
disease-causing changes were identified, leading Takai et al. (1999) to
conclude that mutation in the ACTC gene is a rare cause of dilated
cardiomyopathy, at least in Japanese patients.
Mayosi et al. (1999) studied 57 South African patients with dilated
cardiomyopathy, 56% of whom were of black African origin. No mutation
predicted to produce an alteration in protein was identified in either
the skeletal or cardiac actin genes in any patient.
- Hypertrophic Cardiomyopathy 11
In a large 3-generation family with hypertrophic cardiomyopathy (CMH11;
612098), Mogensen et al. (1999) identified heterozygosity for a missense
mutation in the ACTC1 gene (A295S; 102540.0003) that was located near 2
missense mutations previously identified as causing an inherited form of
dilated cardiomyopathy (CMD1R). The authors stated that ACTC1 was the
first sarcomeric gene described in which mutations are responsible for 2
different cardiomyopathies, and hypothesized that ACTC1 mutations
affecting sarcomere contraction lead to HCM and that mutations affecting
force transmission from the sarcomere to the surrounding syncytium lead
to dilated cardiomyopathy.
Olson et al. (2000) screened the ACTC1 gene in 368 unrelated patients
with sporadic or familial CMH and identified 3 different heterozygous
mutations in 2 sporadic patients with apical CMH (102540.0007 and
102540.0008, respectively) and in a 4-generation family segregating
autosomal dominant CMH (E101K; 102540.0009). None of the mutations was
detected in 150 unrelated controls, and each involved a highly conserved
residue in ACTC1. The authors noted that these and previously identified
CMH-related ACTC1 mutations are likely to affect actin-myosin
interaction and force generation; in contrast, CMD-related ACTC1
mutations (e.g., R312H and E361G) are not located in domains interacting
with the myosin head, but rather occur in a region of the actin monomer
that forms the immobilized end of the actin filament. Olson et al.
(2000) concluded that mutations in ACTC1 can cause either CMH or CMD,
depending on the functional domain of actin that is affected.
In affected members of 2 families segregating autosomal dominant apical
CMH over 3 generations, Arad et al. (2005) identified heterozygosity for
the E101K mutation in the ACTC1 gene.
Monserrat et al. (2007) screened 247 probands with CMH, CMD, or left
ventricular noncompaction (see LVNC4, 613424) for the E101K mutation,
and identified the mutation in 4 probands with CMH, 2 of whom were
previously studied by Arad et al. (2005), and in 1 proband with LVNC. Of
46 family members with CMH, 23 fulfilled criteria for LVNC, 22 were
diagnosed with apical CMH, and 3 had been diagnosed with restrictive
cardiomyopathy. Septal defects were identified in 9 mutation carriers
from 4 families (8 atrial defects and 1 ventricular), and were absent in
relatives without the mutation. Monserrat et al. (2007) concluded that
LVNC and CMH may appear as overlapping entities, and that E101K should
be considered in the genetic diagnosis of LVNC, apical CMH, and septal
defects.
In 2 unrelated children with idiopathic cardiac hypertrophy and presumed
sporadic cardiomyopathy, Morita et al. (2008) identified 2 different
missense mutations in the ACTC1 gene (see, e.g., 102540.0004); 1 of the
children also carried a missense mutation in the MYH7 gene (160760),
which is known to cause CMH1 (192600). The parents were not studied.
- Left Ventricular Noncompaction 4
Klaassen et al. (2008) analyzed 6 sarcomere protein genes in 63
unrelated adult probands with left ventricular noncompaction (see LVNC4;
613424) and no other congenital heart anomalies and identified the E101K
mutation in the ACTC1 gene in 2 probands.
- Atrial Septal Defect 5
Matsson et al. (2008) analyzed the ACTC1 gene in 2 large Swedish
families segregating autosomal dominant secundum atrial septal defect
(ASD5; 612794) and identified heterozygosity for a mutation (M123V;
102540.0005) in the 20 available affected individuals. The authors
studied 408 additional individuals referred for sporadic congenital
heart disease and identified a 17-bp deletion (102540.0006) in the ACTC1
gene in a 10-year-old girl with secundum ASD.
*FIELD* AV
.0001
CARDIOMYOPATHY, DILATED, 1R
ACTC1, ARG312HIS
In a 36-year-old mother and 2 daughters, aged 5 and 2 years, of German
ancestry who had dilated cardiomyopathy (CMD1R; 613424), Olson et al.
(1998) found a G-to-A substitution in codon 312 in exon 5 of the ACTC
gene, resulting in an arg312-to-his (R312H) amino acid substitution. A
15-year-old son likewise had inherited the mutation but had not
developed dilated cardiomyopathy.
.0002
CARDIOMYOPATHY, DILATED, 1R
ACTC1, GLU361GLY
In a family of Swedish Norwegian ancestry, Olson et al. (1998) found
that a father and son, aged 41 and 14 years, respectively, with dilated
cardiomyopathy-1R (613424) carried a GAG (glu)-to-GGG (gly) mutation in
codon 361 in exon 6 of the ACTC gene. In addition, a 34-year-old woman
with a dilated heart and a 9-year-old with borderline heart size also
had inherited the mutation.
.0003
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11
ACTC1, ALA295SER
In a 3-generation family with autosomal dominant hypertrophic
cardiomyopathy (612098), Mogensen et al. (1999) identified a 253G-T
transversion in exon 5 of the ACTC gene resulting in an ala295-to-ser
substitution. The ala at position 295 is conserved in 19 different
species. The expression of the actin mutation in this family gave the
impression of a highly penetrant disease with diverse phenotypes and
variable age of onset. Only 1 individual of 13 family members carrying
the mutant allele was nonpenetrant, and morbidity was low, as only 3 of
the 13 carrying the mutant allele had symptoms of the disease.
.0004
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11
ACTC1, HIS90TYR
In a child with idiopathic cardiac hypertrophy and presumed sporadic
cardiomyopathy (612098) who was negative for mutation in 9 of the known
CMH genes, Morita et al. (2008) identified a heterozygous C-to-T
transition in the ACTC1 gene resulting in a his90-to-tyr (H90Y)
substitution. The parents were not studied. The mutation was not found
in unrelated individuals matched by ancestral origin or in more than
1,000 control chromosomes.
.0005
ATRIAL SEPTAL DEFECT 5
ACTC1, MET123VAL
In 20 affected individuals from 2 Swedish families segregating autosomal
dominant atrial septal defect (ASD5; 612794), Matsson et al. (2008)
identified heterozygosity for a 373A-G transition in exon 2 of the ACTC1
gene, predicted to result in a met123-to-val (M123V) substitution.
Functional analysis of the M123V-mutant protein showed a reduced
affinity for myosin, but retention of actin filament polymerization and
actomyosin motor properties. The mutation was not found in 580 control
samples.
.0006
ATRIAL SEPTAL DEFECT 5
ACTC1, 17-BP DEL, NT251
In a 10-year-old girl with a secundum atrial septal defect (ASD5;
612794), Matsson et al. (2008) identified heterozygosity for a 17-bp
deletion beginning at nucleotide 251 in exon 2 of the ACTC1 gene,
predicted to result in a severely truncated protein of 86 amino acids in
length. The mutation was also identified in her clinically unaffected
43-year-old father, who was found to have an abnormal echocardiogram
with a posteriorly deviated interventricular septum, believed to be
associated with a spontaneously closed perimembranous ventricular septal
defect, causing aortic valve regurgitation. The deletion was not found
in 580 control samples.
.0007
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11
ACTC1, ALA331PRO
In a 21-year-old man with hypertrophic cardiomyopathy (CMH11; 612098),
Olson et al. (2000) identified heterozygosity for a G-C transversion in
exon 6 of the ACTC1 gene, resulting in an ala331-to-pro (A331P)
substitution at a highly conserved residue. The patient presented at 8
years of age with 2 near-syncopal episodes and was diagnosed with
idiopathic CMH. At 10 years of age, he was resuscitated from ventricular
fibrillation that occurred while running, and a defibrillator was
placed. Cardiac evaluation revealed hypertrophy of the septum and left
ventricular apex. His unaffected parents did not carry the mutation, nor
was it found in 150 unrelated controls.
.0008
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11
ACTC1, PRO164ALA
In a 12-year-old boy with hypertrophic cardiomyopathy-11 (612098), Olson
et al. (2000) identified heterozygosity for a C-G transversion in exon 2
of the ACTC1 gene, resulting in a pro164-to-ala (P164A) substitution at
a highly conserved residue. The patient was diagnosed with CMH at 17
months of age due to syncopal episodes. He later had occasional episodes
of chest pain, dyspnea, and near-syncope, and underwent insertion of a
pacemaker. Cardiac evaluation revealed hypertrophy of the septum and
left ventricular apex. His unaffected parents did not carry the
mutation, nor was it found in 150 unrelated controls.
.0009
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11
LEFT VENTRICULAR NONCOMPACTION 4, INCLUDED
ACTC1, GLU101LYS
Using a new numbering system, Arad et al. (2005) designated this
mutation GLU101LYS (E101K).
In 7 affected members of a 4-generation family segregating autosomal
dominant hypertrophic cardiomyopathy (CMH11; 612098), Olson et al.
(2000) identified heterozygosity for a G-A transition in exon 2 of the
ACTC1 gene, resulting in a glu99-to-lys (GLU99LYS) substitution at a
highly conserved residue. Apical left ventricular hypertrophy was
present in 5 cases and a trabeculated apex in 2 cases; 2 individuals
also had marked hypertrophy of the interventricular septum without left
ventricular outflow obstruction, and 1 had an atrial septal defect.
In affected members of 2 families segregating autosomal dominant apical
CMH over 3 generations, Arad et al. (2005) identified heterozygosity for
the E101K mutation in the ACTC1 gene. A shared haplotype was also
identified, providing odds greater than 100:1 that E101K represents a
founding mutation in the 2 families; however, haplotype data indicated
that E101K arose independently in the family reported by Olson et al.
(2000). Of 18 mutation-positive individuals studied by Arad et al.
(2005), 2 individuals, ages 10 and 29 years, had no clinical evidence of
cardiomyopathy. Isolated apical hypertrophy was found in 5 individuals;
11 others also had mild thickening of the basal segments and/or
involvement of the midventricular segment, and 2 also had trabeculation
of the apex. Right ventricular endomyocardial biopsy in 1 patient
revealed myocyte hypertrophy and disarray with extensive replacement
fibrosis that was more marked than that typically seen in CMH associated
with other morphologic patterns of hypertrophy.
Monserrat et al. (2007) screened 247 probands with CMH, dilated
cardiomyopathy (CMD), or left ventricular noncompaction (see LVNC4,
613424) for the E101K mutation, and identified the mutation in 4
probands with CMH and 1 with LVNC. The 5 mutation-positive families, 2
of which were previously studied by Arad et al. (2005), were all from
the same local area in Galicia, Spain, and shared the same 88-bp allele
of the intragenic ACTC1 microsatellite marker that cosegregated with
disease in the families, suggesting a likely founder effect. Of 46
family members with CMH, 23 fulfilled criteria for LVNC, 22 were
diagnosed with apical CMH, and 3 had been diagnosed with restrictive
cardiomyopathy. Septal defects were identified in 9 mutation carriers
from 4 families (8 atrial defects and 1 ventricular), and were absent in
relatives without the mutation. The E101K mutation was not found in 48
unaffected family members. Monserrat et al. (2007) concluded that LVNC
and CMH may appear as overlapping entities, and that E101K should be
considered in the genetic diagnosis of LVNC, apical CMH, and septal
defects.
In a 15-year-old girl and an unrelated 38-year-old woman with LVNC,
Klaassen et al. (2008) identified heterozygosity for the E101K mutation
in the ACTC1 gene. Both had inherited the mutation from their affected
fathers; haplotype analysis excluded a common ancestor. All 4 patients
had noncompaction of the apex and midventricular wall and no other
congenital cardiac anomalies.
*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. Buckingham, M.; Alonso, S.; Barton, P.; Cohen, A.; Daubas, P.;
Garner, I.; Robert, B.; Weydert, A.: Actin and myosin multigene families:
their expression during the formation and maturation of striated muscle. Am.
J. Med. Genet. 25: 623-634, 1986.
3. Crosby, J. L.; Phillips, S. J.; Nadeau, J. H.: The cardiac actin
locus (Actc-1) is not on mouse chromosome 17 but is linked to beta-2-microglobulin
on chromosome 2. Genomics 5: 19-23, 1989.
4. Czosnek, H.; Nudel, U.; Mayer, Y.; Barker, P. E.; Pravtcheva, D.
D.; Ruddle, F. H.; Yaffe, D.: The genes coding for the cardiac muscle
actin, the skeletal muscle actin and the cytoplasmic beta-actin are
located on three different mouse chromosomes. EMBO J. 2: 1977-1979,
1983.
5. Elzinga, M.; Maron, B. J.; Adelstein, R. S.: Human heart and platelet
actins are products of different genes. Science 191: 94-95, 1976.
6. Engel, J. N.; Gunning, P. W.; Kedes, L.: Isolation and characterization
of human actin genes. Proc. Nat. Acad. Sci. 78: 4674-4678, 1981.
7. Firtel, R. A.: Multigene families encoding actin and tubulin. Cell 24:
6-7, 1981.
8. Garner, I.; Minty, A. J.; Alonso, S.; Barton, P. J.; Buckingham,
M. E.: A 5-prime duplication of the alpha-cardiac actin gene in BALB/c
mice is associated with abnormal levels of alpha-cardiac and alpha-skeletal
actin mRNAs in adult cardiac tissue. EMBO J. 5: 2559-2567, 1986.
9. Gunning, P.; Ponte, P.; Kedes, L.; Eddy, R.; Shows, T.: Chromosomal
location of the co-expressed human skeletal and cardiac actin genes. Proc.
Nat. Acad. Sci. 81: 1813-1817, 1984.
10. Hamada, H.; Petrino, M. G.; Kakunaga, T.: Molecular structure
and evolutionary origin of human cardiac muscle actin gene. Proc.
Nat. Acad. Sci. 79: 5901-5905, 1982.
11. Humphries, S. E.; Whittall, R.; Minty, A.; Buckingham, M.; Williamson,
R.: There are approximately 20 actin genes in the human genome. Nucleic
Acids Res. 9: 4895-4908, 1981.
12. Klaassen, S.; Probst, S.; Oechslin, E.; Gerull, B.; Krings, G.;
Schuler, P.; Greutmann, M.; Hurlimann, D.; Yegibasi, M.; Pons, L.;
Gramlich, M.; Drenckhahn, J.-D.; Heuser, A.; Berger, F.; Jenni, R.;
Thierfelder, L.: Mutations in sarcomere protein genes in left ventricular
noncompaction. Circulation 117: 2893-2901, 2008.
13. Kramer, P. L.; Luty, J. A.; Litt, M.: Regional localization of
the gene for cardiac muscle actin (ACTC) on chromosome 15q. Genomics 13:
904-905, 1992.
14. Litt, M.; Luty, J. A.: A hypervariable microsatellite revealed
by in vitro amplification of a dinucleotide repeat within the cardiac
muscle actin gene. Am. J. Hum. Genet. 44: 397-401, 1989.
15. Matsson, H.; Eason, J.; Bookwalter, C. S.; Klar, J.; Gustavsson,
P.; Sunnegardh, J.; Enell, H.; Jonzon, A.; Vikkula, M.; Gutierrez,
I.; Granados-Riveron, J.; Pope, M.; Bu'Lock, F.; Cox, J.; Robinson,
T. E.; Song, F.; Brook, D. J.; Marston, S.; Trybus, K. M.; Dahl, N.
: Alpha-cardiac actin mutations produce atrial septal defects. Hum.
Molec. Genet. 17: 256-265, 2008.
16. Mayosi, B. M.; Khogali, S. S.; Zhang, B.; Watkins, H.: Cardiac
and skeletal actin gene mutations are not a common cause of dilated
cardiomyopathy. J. Med. Genet. 36: 796-797, 1999.
17. Mogensen, J.; Klausen, I. C.; Pedersen, A. K.; Egeblad, H.; Bross,
P.; Kruse, T. A.; Gregersen, N.; Hansen, P. S.; Baandrup, U.; Borglum,
A. D.: Alpha-cardiac actin is a novel disease gene in familial hypertrophic
cardiomyopathy. J. Clin. Invest. 103: R39-R43, 1999.
18. Monserrat, L.; Hermida-Prieto, M.; Fernandez, X.; Rodriguez, I.;
Dumont, C.; Cazon, L.; Cuesta, M. G.; Gonzalez-Juanatey, C.; Peteiro,
J.; Alvarez, N.; Penas-Lado, M.; Castro-Beiras, A.: Mutation in the
alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy,
left ventricular non-compaction, and septal defects. Europ. Heart
J. 28: 1953-1961, 2007.
19. Morita, H.; Rehm, H. L.; Menesses, A.; McDonough, B.; Roberts,
A. E.; Kucherlapati, R.; Towbin, J. A.; Seidman, J. G.; Seidman, C.
E.: Shared genetic causes of cardiac hypertrophy in children and
adults. New Eng. J. Med. 358: 1899-1908, 2008.
20. Olson, T. M.; Doan, T. P.; Kishimoto, N. Y.; Whitby, F. G.; Ackerman,
M. J.; Fananapazir, L.: Inherited and de novo mutations in the cardiac
actin gene cause hypertrophic cardiomyopathy. J. Molec. Cell Cardiol. 32:
1687-1694, 2000.
21. Olson, T. M.; Michels, V. V.; Thibodeau, S. N.; Tai, Y.-S.; Keating,
M. T.: Actin mutations in dilated cardiomyopathy, a heritable form
of heart failure. Science 280: 750-752, 1998.
22. Schwartz, K.; de la Bastie, D.; Bouveret, P.; Oliviero, P.; Alonso,
S.; Buckingham, M.: Alpha-skeletal muscle actin mRNAs accumulate
in hypertrophied adult rat hearts. Circulation Res. 59: 551-555,
1986.
23. Shows, T.; Eddy, R. L.; Haley, L.; Byers, M.; Henry, M.; Gunning,
P.; Ponte, P.; Kedes, L.: The coexpressed genes for human alpha (ACTA)
and cardiac actin (ACTC) are on chromosomes 1 and 15, respectively.
(Abstract) Cytogenet. Cell Genet. 37: 583 only, 1984.
24. Takai, E.; Akita, H.; Shiga, N.; Kanazawa, K.; Yamada, S.; Terashima,
M.; Matsuda, Y.; Iwai, C.; Kawai, K.; Yokota, Y.; Yokoyama, M.: Mutational
analysis of the cardiac actin gene in familial and sporadic dilated
cardiomyopathy. Am. J. Med. Genet. 86: 325-327, 1999.
25. Ueyama, H.; Inazawa, J.; Ariyama, T.; Nishino, H.; Ochiai, Y.;
Ohkubo, I.; Miwa, T.: Reexamination of chromosomal loci of human
muscle actin genes by fluorescence in situ hybridization. Jpn. J.
Hum. Genet. 40: 145-148, 1995.
26. Weber, J. L.; May, P. E.: Abundant class of human DNA polymorphisms
which can be typed using the polymerase chain reaction. Am. J. Hum.
Genet. 44: 388-396, 1989.
27. Weydert, A.; Robert, B.; Alonso, S.; Caravatti, M.; Cohen, A.;
Daubas, P.; Minty, A.; Buckingham, M.: Multigene families of contractile
proteins: the actins and myosins. (Abstract) Sixth Int. Cong. Hum.
Genet., Jerusalem 39 only, 1981.
*FIELD* CN
Marla J. F. O'Neill - updated: 06/07/2010
Marla J. F. O'Neill - updated: 5/4/2009
Marla J. F. O'Neill - updated: 6/4/2008
Ada Hamosh - updated: 3/17/2000
Michael J. Wright - updated: 2/4/2000
Victor A. McKusick - updated: 10/28/1999
Victor A. McKusick - updated: 4/28/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 06/07/2010
wwang: 5/20/2009
terry: 5/4/2009
carol: 6/5/2008
carol: 6/4/2008
terry: 6/4/2008
carol: 11/20/2007
carol: 9/10/2007
wwang: 2/23/2006
alopez: 3/22/2000
terry: 3/17/2000
alopez: 2/4/2000
carol: 11/4/1999
terry: 10/28/1999
carol: 3/22/1999
alopez: 4/28/1998
terry: 4/28/1998
carol: 6/20/1997
mark: 11/27/1996
terry: 6/16/1995
carol: 11/18/1994
carol: 10/13/1993
carol: 8/25/1992
carol: 6/29/1992
carol: 3/20/1992
MIM
612098
*RECORD*
*FIELD* NO
612098
*FIELD* TI
#612098 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11; CMH11
*FIELD* TX
A number sign (#) is used with this entry because familial hypertrophic
read morecardiomyopathy-11 is caused by heterozygous mutation in the ACTC1 gene
(102540) on chromosome 15q14.
For a general phenotypic description and a discussion of genetic
heterogeneity of familial hypertrophic cardiomyopathy, see CMH1
(192600).
CLINICAL FEATURES
Olson et al. (2000) studied 2 sporadic patients with apical hypertrophic
cardiomyopathy (CMH) and a 4-generation family segregating autosomal
dominant CMH. The 2 sporadic patients had early-onset nonobstructive CMH
involving the interventricular septum and left ventricular apex; left
ventricular dimensions and shortening fractions were normal,
demonstrating no features of dilated cardiomyopathy (CMD; see 613424).
In the 4-generation kindred, the cardiomyopathy was later in onset and
involved apical left ventricular hypertrophy in 5 cases and a
trabeculated apex in 2 cases; 2 patients also had marked hypertrophy of
the interventricular septum without outflow tract obstruction. Left
ventricular dimensions were increased with normal shortening fractions
in 2 patients; Olson et al. (2000) noted that in one of them, the
dilation might have been a consequence of post-cardiac arrest myocardial
injury and/or late-stage CMH, and in the other, a 25-year-old
asymptomatic competitive athlete with a trabeculated apex and repaired
atrial septal defect, the dilation might have been physiologic.
Arad et al. (2005) studied 18 mutation-positive members of 2 families
segregating autosomal dominant apical CMH (see MOLECULAR GENETICS
section) and found that 2 individuals, aged 10 and 29 years, had no
clinical evidence of cardiomyopathy. Isolated apical hypertrophy was
found in 5 individuals; 11 others also had mild thickening of the basal
segments and/or involvement of the midventricular segment, and 2 also
had trabeculation of the apex. Systolic ventricular function was
preserved in all affected individuals; none had an outflow or
midcavitary gradient, and 2 had significant mitral regurgitation. Right
ventricular endomyocardial biopsy in a 43-year-old man who underwent
cardiac catheterization due to increasing dyspnea revealed myocyte
hypertrophy and disarray with extensive replacement fibrosis that was
more marked than that typically seen in CMH associated with other
morphologic patterns of hypertrophy. Electrocardiograms (ECGs) in
affected family members showed voltage criteria for left ventricular
hypertrophy (LVH) in only 2 individuals; T-wave inversion and ST-T
segment abnormalities were present in 8 individuals. Other ECG
abnormalities included 3 patients with atrial fibrillation, 3 with
first-degree heart block, and 2 with short PR intervals without delta
waves. One asymptomatic individual also had pathologic Q waves
consistent with apical infarction. Disease progression was slow in the
affected individuals, with increasing symptoms of angina and dyspnea;
some elderly family members developed congestive heart failure in the
context of atrial fibrillation, but none had a myocardial infarction,
history of life-threatening arrhythmia, or sudden cardiac death.
MAPPING
Mogensen et al. (1999) performed linkage analysis in a large family with
hypertrophic cardiomyopathy and excluded linkage to known CMH loci, with
lod scores varying from -2.5 to -6.0. Further linkage analysis of
plausible candidate genes highly expressed in the human heart yielded a
maximum lod score of 3.6 at ACTC1.
MOLECULAR GENETICS
In a large 3-generation family with hypertrophic cardiomyopathy,
Mogensen et al. (1999) identified heterozygosity for a missense mutation
in the ACTC1 gene (102540.0003). The 13 affected family members had
diverse phenotypes with variable age of onset and low morbidity; only 3
mutation-positive individuals had symptoms of the disease, although some
of the others had abnormal electrocardiograms and most had a septal
bulge in the left ventricular outflow tract. One woman had recurrent
episodes of palpitations and syncope at 32 years of age and was
diagnosed with Wolff-Parkinson-White syndrome (194200); an
echocardiogram showed borderline hypertrophy which enlarged
significantly over the next 7 years, from 12 mm to 19 mm. One boy had
early onset of disease, presenting at 4 years of age with a heart murmur
caused by a septal bulge. Only 1 mutation-positive family member was
nonpenetrant, an asymptomatic 28-year-old man with no evidence of
cardiac disease on ECG or echocardiogram.
Olson et al. (2000) screened the ACTC1 gene in 368 unrelated patients
with sporadic or familial CMH and identified 3 different heterozygous
mutations in 2 sporadic patients with apical CMH (102540.0007 and
102540.0008, respectively) and in a 4-generation family segregating
autosomal dominant CMH (E101K; 102540.0009).
In affected members of 2 families segregating autosomal dominant apical
CMH over 3 generations, Arad et al. (2005) identified heterozygosity for
the E101K mutation in the ACTC1 gene. A shared haplotype was also
identified, providing odds greater than 100:1 that E101K represents a
founder mutation in the 2 families; however, haplotype data indicated
that E101K arose independently in the family reported by Olson et al.
(2000).
Monserrat et al. (2007) screened 247 probands with CMH, dilated
cardiomyopathy (see CMD1R, 613434), or left ventricular noncompaction
(see LVNC4, 613434) for the E101K mutation in the ACTC1 gene and
identified the mutation in 4 probands diagnosed with CMH and 1 with
LVNC. Of 46 mutation-positive family members, all had increased maximum
left ventricular wall thickness, usually with prominent trabeculations
and deep invaginations in the thickened segments; 23 patients fulfilled
criteria for LVNC, 22 had been diagnosed with apical CMH, and 3 with
restrictive cardiomyopathy. Septal defects were identified in 9 mutation
carriers from 4 families, including 8 atrial defects (see ASD5; 612794)
and 1 ventricular defect, and were absent in relatives without the
mutation. Monserrat et al. (2007) concluded that LVNC and CMH may appear
as overlapping entities, and that the E101K mutation in ACTC1 should be
considered in the genetic diagnosis of LVNC, apical CMH, and septal
defects.
In 2 unrelated children with idiopathic cardiac hypertrophy that
developed before 15 years of age, who were presumed to have sporadic
cardiomyopathy, Morita et al. (2008) identified 2 different missense
mutations in the ACTC1 gene (see, e.g., 102540.0004). One of the
children also carried a missense mutation in the MYH7 gene (160760),
which is known to cause CMH1. The parents were not studied.
*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. Mogensen, J.; Klausen, I. C.; Pedersen, A. K.; Egeblad, H.; Bross,
P.; Kruse, T. A.; Gregersen, N.; Hansen, P. S.; Baandrup, U.; Borglum,
A. D.: Alpha-cardiac actin is a novel disease gene in familial hypertrophic
cardiomyopathy. J. Clin. Invest. 103: R39-R43, 1999.
3. Monserrat, L.; Hermida-Prieto, M.; Fernandez, X.; Rodriguez, I.;
Dumont, C.; Cazon, L.; Cuesta, M. G.; Gonzalez-Juanatey, C.; Peteiro,
J.; Alvarez, N.; Penas-Lado, M.; Castro-Beiras, A.: Mutation in the
alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy,
left ventricular non-compaction, and septal defects. Europ. Heart
J. 28: 1953-1961, 2007.
4. Morita, H.; Rehm, H. L.; Menesses, A.; McDonough, B.; Roberts,
A. E.; Kucherlapati, R.; Towbin, J. A.; Seidman, J. G.; Seidman, C.
E.: Shared genetic causes of cardiac hypertrophy in children and
adults. New Eng. J. Med. 358: 1899-1908, 2008.
5. Olson, T. M.; Doan, T. P.; Kishimoto, N. Y.; Whitby, F. G.; Ackerman,
M. J.; Fananapazir, L.: Inherited and de novo mutations in the cardiac
actin gene cause hypertrophic cardiomyopathy. J. Molec. Cell Cardiol. 32:
1687-1694, 2000.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy;
Septal bulge of left ventricular outflow tract;
Wolff-Parkinson-White arrhythmia (rare)
MISCELLANEOUS:
Early onset in some patients;
Highly penetrant, but low morbidity
MOLECULAR BASIS:
Caused by mutation in the cardiac muscle alpha actin gene (ACTC1,
102540.0003)
*FIELD* CD
Marla J. F. O'Neill: 1/28/2009
*FIELD* ED
joanna: 01/28/2009
*FIELD* CN
Marla J. F. O'Neill - updated: 06/07/2010
*FIELD* CD
Marla J. F. O'Neill: 6/4/2008
*FIELD* ED
carol: 06/07/2010
carol: 6/5/2008
carol: 6/4/2008
*RECORD*
*FIELD* NO
612098
*FIELD* TI
#612098 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 11; CMH11
*FIELD* TX
A number sign (#) is used with this entry because familial hypertrophic
read morecardiomyopathy-11 is caused by heterozygous mutation in the ACTC1 gene
(102540) on chromosome 15q14.
For a general phenotypic description and a discussion of genetic
heterogeneity of familial hypertrophic cardiomyopathy, see CMH1
(192600).
CLINICAL FEATURES
Olson et al. (2000) studied 2 sporadic patients with apical hypertrophic
cardiomyopathy (CMH) and a 4-generation family segregating autosomal
dominant CMH. The 2 sporadic patients had early-onset nonobstructive CMH
involving the interventricular septum and left ventricular apex; left
ventricular dimensions and shortening fractions were normal,
demonstrating no features of dilated cardiomyopathy (CMD; see 613424).
In the 4-generation kindred, the cardiomyopathy was later in onset and
involved apical left ventricular hypertrophy in 5 cases and a
trabeculated apex in 2 cases; 2 patients also had marked hypertrophy of
the interventricular septum without outflow tract obstruction. Left
ventricular dimensions were increased with normal shortening fractions
in 2 patients; Olson et al. (2000) noted that in one of them, the
dilation might have been a consequence of post-cardiac arrest myocardial
injury and/or late-stage CMH, and in the other, a 25-year-old
asymptomatic competitive athlete with a trabeculated apex and repaired
atrial septal defect, the dilation might have been physiologic.
Arad et al. (2005) studied 18 mutation-positive members of 2 families
segregating autosomal dominant apical CMH (see MOLECULAR GENETICS
section) and found that 2 individuals, aged 10 and 29 years, had no
clinical evidence of cardiomyopathy. Isolated apical hypertrophy was
found in 5 individuals; 11 others also had mild thickening of the basal
segments and/or involvement of the midventricular segment, and 2 also
had trabeculation of the apex. Systolic ventricular function was
preserved in all affected individuals; none had an outflow or
midcavitary gradient, and 2 had significant mitral regurgitation. Right
ventricular endomyocardial biopsy in a 43-year-old man who underwent
cardiac catheterization due to increasing dyspnea revealed myocyte
hypertrophy and disarray with extensive replacement fibrosis that was
more marked than that typically seen in CMH associated with other
morphologic patterns of hypertrophy. Electrocardiograms (ECGs) in
affected family members showed voltage criteria for left ventricular
hypertrophy (LVH) in only 2 individuals; T-wave inversion and ST-T
segment abnormalities were present in 8 individuals. Other ECG
abnormalities included 3 patients with atrial fibrillation, 3 with
first-degree heart block, and 2 with short PR intervals without delta
waves. One asymptomatic individual also had pathologic Q waves
consistent with apical infarction. Disease progression was slow in the
affected individuals, with increasing symptoms of angina and dyspnea;
some elderly family members developed congestive heart failure in the
context of atrial fibrillation, but none had a myocardial infarction,
history of life-threatening arrhythmia, or sudden cardiac death.
MAPPING
Mogensen et al. (1999) performed linkage analysis in a large family with
hypertrophic cardiomyopathy and excluded linkage to known CMH loci, with
lod scores varying from -2.5 to -6.0. Further linkage analysis of
plausible candidate genes highly expressed in the human heart yielded a
maximum lod score of 3.6 at ACTC1.
MOLECULAR GENETICS
In a large 3-generation family with hypertrophic cardiomyopathy,
Mogensen et al. (1999) identified heterozygosity for a missense mutation
in the ACTC1 gene (102540.0003). The 13 affected family members had
diverse phenotypes with variable age of onset and low morbidity; only 3
mutation-positive individuals had symptoms of the disease, although some
of the others had abnormal electrocardiograms and most had a septal
bulge in the left ventricular outflow tract. One woman had recurrent
episodes of palpitations and syncope at 32 years of age and was
diagnosed with Wolff-Parkinson-White syndrome (194200); an
echocardiogram showed borderline hypertrophy which enlarged
significantly over the next 7 years, from 12 mm to 19 mm. One boy had
early onset of disease, presenting at 4 years of age with a heart murmur
caused by a septal bulge. Only 1 mutation-positive family member was
nonpenetrant, an asymptomatic 28-year-old man with no evidence of
cardiac disease on ECG or echocardiogram.
Olson et al. (2000) screened the ACTC1 gene in 368 unrelated patients
with sporadic or familial CMH and identified 3 different heterozygous
mutations in 2 sporadic patients with apical CMH (102540.0007 and
102540.0008, respectively) and in a 4-generation family segregating
autosomal dominant CMH (E101K; 102540.0009).
In affected members of 2 families segregating autosomal dominant apical
CMH over 3 generations, Arad et al. (2005) identified heterozygosity for
the E101K mutation in the ACTC1 gene. A shared haplotype was also
identified, providing odds greater than 100:1 that E101K represents a
founder mutation in the 2 families; however, haplotype data indicated
that E101K arose independently in the family reported by Olson et al.
(2000).
Monserrat et al. (2007) screened 247 probands with CMH, dilated
cardiomyopathy (see CMD1R, 613434), or left ventricular noncompaction
(see LVNC4, 613434) for the E101K mutation in the ACTC1 gene and
identified the mutation in 4 probands diagnosed with CMH and 1 with
LVNC. Of 46 mutation-positive family members, all had increased maximum
left ventricular wall thickness, usually with prominent trabeculations
and deep invaginations in the thickened segments; 23 patients fulfilled
criteria for LVNC, 22 had been diagnosed with apical CMH, and 3 with
restrictive cardiomyopathy. Septal defects were identified in 9 mutation
carriers from 4 families, including 8 atrial defects (see ASD5; 612794)
and 1 ventricular defect, and were absent in relatives without the
mutation. Monserrat et al. (2007) concluded that LVNC and CMH may appear
as overlapping entities, and that the E101K mutation in ACTC1 should be
considered in the genetic diagnosis of LVNC, apical CMH, and septal
defects.
In 2 unrelated children with idiopathic cardiac hypertrophy that
developed before 15 years of age, who were presumed to have sporadic
cardiomyopathy, Morita et al. (2008) identified 2 different missense
mutations in the ACTC1 gene (see, e.g., 102540.0004). One of the
children also carried a missense mutation in the MYH7 gene (160760),
which is known to cause CMH1. The parents were not studied.
*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. Mogensen, J.; Klausen, I. C.; Pedersen, A. K.; Egeblad, H.; Bross,
P.; Kruse, T. A.; Gregersen, N.; Hansen, P. S.; Baandrup, U.; Borglum,
A. D.: Alpha-cardiac actin is a novel disease gene in familial hypertrophic
cardiomyopathy. J. Clin. Invest. 103: R39-R43, 1999.
3. Monserrat, L.; Hermida-Prieto, M.; Fernandez, X.; Rodriguez, I.;
Dumont, C.; Cazon, L.; Cuesta, M. G.; Gonzalez-Juanatey, C.; Peteiro,
J.; Alvarez, N.; Penas-Lado, M.; Castro-Beiras, A.: Mutation in the
alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy,
left ventricular non-compaction, and septal defects. Europ. Heart
J. 28: 1953-1961, 2007.
4. Morita, H.; Rehm, H. L.; Menesses, A.; McDonough, B.; Roberts,
A. E.; Kucherlapati, R.; Towbin, J. A.; Seidman, J. G.; Seidman, C.
E.: Shared genetic causes of cardiac hypertrophy in children and
adults. New Eng. J. Med. 358: 1899-1908, 2008.
5. Olson, T. M.; Doan, T. P.; Kishimoto, N. Y.; Whitby, F. G.; Ackerman,
M. J.; Fananapazir, L.: Inherited and de novo mutations in the cardiac
actin gene cause hypertrophic cardiomyopathy. J. Molec. Cell Cardiol. 32:
1687-1694, 2000.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy;
Septal bulge of left ventricular outflow tract;
Wolff-Parkinson-White arrhythmia (rare)
MISCELLANEOUS:
Early onset in some patients;
Highly penetrant, but low morbidity
MOLECULAR BASIS:
Caused by mutation in the cardiac muscle alpha actin gene (ACTC1,
102540.0003)
*FIELD* CD
Marla J. F. O'Neill: 1/28/2009
*FIELD* ED
joanna: 01/28/2009
*FIELD* CN
Marla J. F. O'Neill - updated: 06/07/2010
*FIELD* CD
Marla J. F. O'Neill: 6/4/2008
*FIELD* ED
carol: 06/07/2010
carol: 6/5/2008
carol: 6/4/2008
MIM
612794
*RECORD*
*FIELD* NO
612794
*FIELD* TI
#612794 ATRIAL SEPTAL DEFECT 5; ASD5
*FIELD* TX
A number sign (#) is used with this entry because the phenotype can be
read morecaused by mutation in the ACTC1 gene (102540).
For a phenotypic description and discussion of genetic heterogeneity in
atrial septal defect, see ASD1 (108800).
MAPPING
Matsson et al. (2008) studied 2 large Swedish families segregating
autosomal dominant isolated secundum atrial septal defect (ASD) with
variable clinical expression. Genotyping with microsatellite markers in
'family 1' revealed a specific haplotype in all affected individuals
spanning a 15.1-cM region of chromosome 15q13-q21; analysis of 'family
2' identified a minimal haplotype with significant linkage to ASD
consisting of markers GT44248, GATA12322, and ACTC. All affected
individuals genotyped had identical allele sizes for the marker
haplotype, suggesting a shared ancestral mutation for the 2 families. A
2-point lod score of 4.8 was obtained for marker ACTC, located within
intron 4 of the ACTC1 gene.
MOLECULAR GENETICS
Matsson et al. (2008) analyzed the ACTC1 gene in 2 large Swedish
families segregating autosomal dominant ASD and identified
heterozygosity for a mutation (M123V; 102540.0005) in the 20 available
affected individuals. The authors studied 408 additional individuals
referred for sporadic congenital heart disease and identified a 17-bp
deletion in the ACTC1 gene in a 10-year-old girl with secundum ASD
(102540.0006); the mutation was also identified in her clinically
unaffected 43-year-old father, who was found to have an abnormal
echocardiogram with a posteriorly deviated interventricular septum,
believed to be associated with a spontaneously closed perimembranous
ventricular septal defect, causing aortic valve regurgitation. Neither
mutation was found in 580 control samples.
*FIELD* RF
1. Matsson, H.; Eason, J.; Bookwalter, C. S.; Klar, J.; Gustavsson,
P.; Sunnegardh, J.; Enell, H.; Jonzon, A.; Vikkula, M.; Gutierrez,
I.; Granados-Riveron, J.; Pope, M.; Bu'Lock, F.; Cox, J.; Robinson,
T. E.; Song, F.; Brook, D. J.; Marston, S.; Trybus, K. M.; Dahl, N.
: Alpha-cardiac actin mutations produce atrial septal defects. Hum.
Molec. Genet. 17: 256-265, 2008.
*FIELD* CD
Marla J. F. O'Neill: 5/20/2009
*FIELD* ED
wwang: 05/20/2009
wwang: 5/20/2009
*RECORD*
*FIELD* NO
612794
*FIELD* TI
#612794 ATRIAL SEPTAL DEFECT 5; ASD5
*FIELD* TX
A number sign (#) is used with this entry because the phenotype can be
read morecaused by mutation in the ACTC1 gene (102540).
For a phenotypic description and discussion of genetic heterogeneity in
atrial septal defect, see ASD1 (108800).
MAPPING
Matsson et al. (2008) studied 2 large Swedish families segregating
autosomal dominant isolated secundum atrial septal defect (ASD) with
variable clinical expression. Genotyping with microsatellite markers in
'family 1' revealed a specific haplotype in all affected individuals
spanning a 15.1-cM region of chromosome 15q13-q21; analysis of 'family
2' identified a minimal haplotype with significant linkage to ASD
consisting of markers GT44248, GATA12322, and ACTC. All affected
individuals genotyped had identical allele sizes for the marker
haplotype, suggesting a shared ancestral mutation for the 2 families. A
2-point lod score of 4.8 was obtained for marker ACTC, located within
intron 4 of the ACTC1 gene.
MOLECULAR GENETICS
Matsson et al. (2008) analyzed the ACTC1 gene in 2 large Swedish
families segregating autosomal dominant ASD and identified
heterozygosity for a mutation (M123V; 102540.0005) in the 20 available
affected individuals. The authors studied 408 additional individuals
referred for sporadic congenital heart disease and identified a 17-bp
deletion in the ACTC1 gene in a 10-year-old girl with secundum ASD
(102540.0006); the mutation was also identified in her clinically
unaffected 43-year-old father, who was found to have an abnormal
echocardiogram with a posteriorly deviated interventricular septum,
believed to be associated with a spontaneously closed perimembranous
ventricular septal defect, causing aortic valve regurgitation. Neither
mutation was found in 580 control samples.
*FIELD* RF
1. Matsson, H.; Eason, J.; Bookwalter, C. S.; Klar, J.; Gustavsson,
P.; Sunnegardh, J.; Enell, H.; Jonzon, A.; Vikkula, M.; Gutierrez,
I.; Granados-Riveron, J.; Pope, M.; Bu'Lock, F.; Cox, J.; Robinson,
T. E.; Song, F.; Brook, D. J.; Marston, S.; Trybus, K. M.; Dahl, N.
: Alpha-cardiac actin mutations produce atrial septal defects. Hum.
Molec. Genet. 17: 256-265, 2008.
*FIELD* CD
Marla J. F. O'Neill: 5/20/2009
*FIELD* ED
wwang: 05/20/2009
wwang: 5/20/2009
MIM
613424
*RECORD*
*FIELD* NO
613424
*FIELD* TI
#613424 CARDIOMYOPATHY, DILATED, 1R; CMD1R
LEFT VENTRICULAR NONCOMPACTION 4, INCLUDED; LVNC4, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because this form of dilated
cardiomyopathy (CMD1R) is caused by heterozygous mutation in the ACTC1
gene (102540) on chromosome 15q14.
Mutation in the ACTC1 gene has also been associated with left
ventricular noncompaction (LVNC4), hypertrophic cardiomyopathy (CMH11;
612098), and atrial septal defects (ASD5; 612794).
For a general phenotypic description and a discussion of genetic
heterogeneity of dilated cardiomyopathy, see CMD1A (115200); for a
similar discussion of left ventricular noncompaction, see LVNC1
(604169).
CLINICAL FEATURES
Olson et al. (1998) studied 2 unrelated families with autosomal dominant
idiopathic dilated cardiomyopathy (CMD), one of German ancestry and the
other of Swedish Norwegian ancestry. Families were phenotypically
characterized by echocardiography, with CMD being defined as left
ventricular end-diastolic dimension (LVEDD) greater than the 95th
percentile for age and body surface area, and shortening fraction less
than 28%. Individuals in both families had variable age at diagnosis (1
to 41 years), similar to other CMD families, with age at diagnosis
differing by as much as 20 to 50 years. Heart biopsy specimens from the
proband of each family revealed histopathologic findings consistent with
CMD, showing moderate focal interstitial fibrosis and myocyte
hypertrophy, but no evidence of myocarditis or of the myofibrillar
disarray seen in hypertrophic cardiomyopathy (CMH).
MOLECULAR GENETICS
In affected members of 2 unrelated families with dilated cardiomyopathy,
Olson et al. (1998) identified heterozygosity for 2 different mutations
in the ACTC1 gene (102540.0001 and 102540.0002, respectively).
Takai et al. (1999) analyzed the ACTC1 gene in 136 Japanese CMD
patients, but found no disease-causing mutations. They concluded that
mutation in the ACTC1 gene is a rare cause of CMD, at least in Japanese
patients.
Mayosi et al. (1999) studied 57 South African patients with dilated
cardiomyopathy, 56% of whom were of black African origin. No mutation
predicted to produce an alteration in protein was identified in either
the skeletal or cardiac actin genes in any patient.
- Left Ventricular Noncompaction 4
Monserrat et al. (2007) screened 247 probands with CMD, hypertrophic
cardiomyopathy (see CMH11, 612098), or left ventricular noncompaction
(LVNC) for the E101K mutation in the ACTC1 gene (102540.0009) and
identified the mutation in 4 probands diagnosed with CMH and 1 with
LVNC. The 5 mutation-positive families, 2 of which were previously
studied by Arad et al. (2005), were all from the same local area in
Galicia, Spain, and shared the same 88-bp allele of the intragenic ACTC1
microsatellite marker that cosegregated with disease in the families,
suggesting a likely founder effect. All 46 mutation-positive members of
the 5 families had increased maximum left ventricular wall thickness,
usually with prominent trabeculations and deep invaginations in the
thickened segments, and 23 patients fulfilled criteria for LVNC; 22 were
diagnosed with apical CMH, and 3 with restrictive cardiomyopathy. Septal
defects were identified in 9 mutation carriers from 4 families,
including 8 atrial defects and 1 ventricular defect, and were absent in
relatives without the mutation. Monserrat et al. (2007) concluded that
LVNC and CMH may appear as overlapping entities, and that the E101K
mutation in ACTC1 should be considered in the genetic diagnosis of LVNC,
apical CMH, and septal defects.
Klaassen et al. (2008) analyzed 6 genes encoding sarcomere proteins in
63 unrelated adult probands with LVNC but no other congenital heart
anomalies, and identified the E101K mutation in the ACTC1 gene in a
15-year-old girl and a 38-year-old woman. Both had inherited the
mutation from their affected fathers; haplotype analysis excluded a
common ancestor. All 4 patients had noncompaction of the apex and
midventricular wall. The 15-year-old girl, who was originally diagnosed
with CMH, had syncope and hypoxic brain damage and underwent pacemaker
implantation; her 58-year-old father had syncope, congestive heart
failure (CHF), and pulmonary hypertension (PHT). The 38-year-old woman
had CHF and PHT, whereas her 73-year-old father had no cardiovascular
complications.
*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. Klaassen, S.; Probst, S.; Oechslin, E.; Gerull, B.; Krings, G.;
Schuler, P.; Greutmann, M.; Hurlimann, D.; Yegibasi, M.; Pons, L.;
Gramlich, M.; Drenckhahn, J.-D.; Heuser, A.; Berger, F.; Jenni, R.;
Thierfelder, L.: Mutations in sarcomere protein genes in left ventricular
noncompaction. Circulation 117: 2893-2901, 2008.
3. Mayosi, B. M.; Khogali, S. S.; Zhang, B.; Watkins, H.: Cardiac
and skeletal actin gene mutations are not a common cause of dilated
cardiomyopathy. J. Med. Genet. 36: 796-797, 1999.
4. Monserrat, L.; Hermida-Prieto, M.; Fernandez, X.; Rodriguez, I.;
Dumont, C.; Cazon, L.; Cuesta, M. G.; Gonzalez-Juanatey, C.; Peteiro,
J.; Alvarez, N.; Penas-Lado, M.; Castro-Beiras, A.: Mutation in the
alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy,
left ventricular non-compaction, and septal defects. Europ. Heart
J. 28: 1953-1961, 2007.
5. Olson, T. M.; Michels, V. V.; Thibodeau, S. N.; Tai, Y.-S.; Keating,
M. T.: Actin mutations in dilated cardiomyopathy, a heritable form
of heart failure. Science 280: 750-752, 1998.
6. Takai, E.; Akita, H.; Shiga, N.; Kanazawa, K.; Yamada, S.; Terashima,
M.; Matsuda, Y.; Iwai, C.; Kawai, K.; Yokota, Y.; Yokoyama, M.: Mutational
analysis of the cardiac actin gene in familial and sporadic dilated
cardiomyopathy. Am. J. Med. Genet. 86: 325-327, 1999.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Left ventricular dilation;
Myocyte hypertrophy;
Congestive heart failure;
Left ventricular noncompaction (in some patients);
Left ventricular hypertrophy (in some patients);
Restrictive cardiomyopathy (in some patients);
Ventricular arrhythmia (in some patients)
MOLECULAR BASIS:
Caused by mutation in the actin, alpha, cardiac muscle gene (ACTC1,
102540.0001)
*FIELD* CD
Marla J. F. O'Neill: 6/16/2010
*FIELD* ED
joanna: 06/16/2010
*FIELD* CD
Marla J. F. O'Neill: 6/4/2010
*FIELD* ED
carol: 06/07/2010
*RECORD*
*FIELD* NO
613424
*FIELD* TI
#613424 CARDIOMYOPATHY, DILATED, 1R; CMD1R
LEFT VENTRICULAR NONCOMPACTION 4, INCLUDED; LVNC4, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because this form of dilated
cardiomyopathy (CMD1R) is caused by heterozygous mutation in the ACTC1
gene (102540) on chromosome 15q14.
Mutation in the ACTC1 gene has also been associated with left
ventricular noncompaction (LVNC4), hypertrophic cardiomyopathy (CMH11;
612098), and atrial septal defects (ASD5; 612794).
For a general phenotypic description and a discussion of genetic
heterogeneity of dilated cardiomyopathy, see CMD1A (115200); for a
similar discussion of left ventricular noncompaction, see LVNC1
(604169).
CLINICAL FEATURES
Olson et al. (1998) studied 2 unrelated families with autosomal dominant
idiopathic dilated cardiomyopathy (CMD), one of German ancestry and the
other of Swedish Norwegian ancestry. Families were phenotypically
characterized by echocardiography, with CMD being defined as left
ventricular end-diastolic dimension (LVEDD) greater than the 95th
percentile for age and body surface area, and shortening fraction less
than 28%. Individuals in both families had variable age at diagnosis (1
to 41 years), similar to other CMD families, with age at diagnosis
differing by as much as 20 to 50 years. Heart biopsy specimens from the
proband of each family revealed histopathologic findings consistent with
CMD, showing moderate focal interstitial fibrosis and myocyte
hypertrophy, but no evidence of myocarditis or of the myofibrillar
disarray seen in hypertrophic cardiomyopathy (CMH).
MOLECULAR GENETICS
In affected members of 2 unrelated families with dilated cardiomyopathy,
Olson et al. (1998) identified heterozygosity for 2 different mutations
in the ACTC1 gene (102540.0001 and 102540.0002, respectively).
Takai et al. (1999) analyzed the ACTC1 gene in 136 Japanese CMD
patients, but found no disease-causing mutations. They concluded that
mutation in the ACTC1 gene is a rare cause of CMD, at least in Japanese
patients.
Mayosi et al. (1999) studied 57 South African patients with dilated
cardiomyopathy, 56% of whom were of black African origin. No mutation
predicted to produce an alteration in protein was identified in either
the skeletal or cardiac actin genes in any patient.
- Left Ventricular Noncompaction 4
Monserrat et al. (2007) screened 247 probands with CMD, hypertrophic
cardiomyopathy (see CMH11, 612098), or left ventricular noncompaction
(LVNC) for the E101K mutation in the ACTC1 gene (102540.0009) and
identified the mutation in 4 probands diagnosed with CMH and 1 with
LVNC. The 5 mutation-positive families, 2 of which were previously
studied by Arad et al. (2005), were all from the same local area in
Galicia, Spain, and shared the same 88-bp allele of the intragenic ACTC1
microsatellite marker that cosegregated with disease in the families,
suggesting a likely founder effect. All 46 mutation-positive members of
the 5 families had increased maximum left ventricular wall thickness,
usually with prominent trabeculations and deep invaginations in the
thickened segments, and 23 patients fulfilled criteria for LVNC; 22 were
diagnosed with apical CMH, and 3 with restrictive cardiomyopathy. Septal
defects were identified in 9 mutation carriers from 4 families,
including 8 atrial defects and 1 ventricular defect, and were absent in
relatives without the mutation. Monserrat et al. (2007) concluded that
LVNC and CMH may appear as overlapping entities, and that the E101K
mutation in ACTC1 should be considered in the genetic diagnosis of LVNC,
apical CMH, and septal defects.
Klaassen et al. (2008) analyzed 6 genes encoding sarcomere proteins in
63 unrelated adult probands with LVNC but no other congenital heart
anomalies, and identified the E101K mutation in the ACTC1 gene in a
15-year-old girl and a 38-year-old woman. Both had inherited the
mutation from their affected fathers; haplotype analysis excluded a
common ancestor. All 4 patients had noncompaction of the apex and
midventricular wall. The 15-year-old girl, who was originally diagnosed
with CMH, had syncope and hypoxic brain damage and underwent pacemaker
implantation; her 58-year-old father had syncope, congestive heart
failure (CHF), and pulmonary hypertension (PHT). The 38-year-old woman
had CHF and PHT, whereas her 73-year-old father had no cardiovascular
complications.
*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. Klaassen, S.; Probst, S.; Oechslin, E.; Gerull, B.; Krings, G.;
Schuler, P.; Greutmann, M.; Hurlimann, D.; Yegibasi, M.; Pons, L.;
Gramlich, M.; Drenckhahn, J.-D.; Heuser, A.; Berger, F.; Jenni, R.;
Thierfelder, L.: Mutations in sarcomere protein genes in left ventricular
noncompaction. Circulation 117: 2893-2901, 2008.
3. Mayosi, B. M.; Khogali, S. S.; Zhang, B.; Watkins, H.: Cardiac
and skeletal actin gene mutations are not a common cause of dilated
cardiomyopathy. J. Med. Genet. 36: 796-797, 1999.
4. Monserrat, L.; Hermida-Prieto, M.; Fernandez, X.; Rodriguez, I.;
Dumont, C.; Cazon, L.; Cuesta, M. G.; Gonzalez-Juanatey, C.; Peteiro,
J.; Alvarez, N.; Penas-Lado, M.; Castro-Beiras, A.: Mutation in the
alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy,
left ventricular non-compaction, and septal defects. Europ. Heart
J. 28: 1953-1961, 2007.
5. Olson, T. M.; Michels, V. V.; Thibodeau, S. N.; Tai, Y.-S.; Keating,
M. T.: Actin mutations in dilated cardiomyopathy, a heritable form
of heart failure. Science 280: 750-752, 1998.
6. Takai, E.; Akita, H.; Shiga, N.; Kanazawa, K.; Yamada, S.; Terashima,
M.; Matsuda, Y.; Iwai, C.; Kawai, K.; Yokota, Y.; Yokoyama, M.: Mutational
analysis of the cardiac actin gene in familial and sporadic dilated
cardiomyopathy. Am. J. Med. Genet. 86: 325-327, 1999.
*FIELD* CS
INHERITANCE:
Autosomal dominant
CARDIOVASCULAR:
[Heart];
Left ventricular dilation;
Myocyte hypertrophy;
Congestive heart failure;
Left ventricular noncompaction (in some patients);
Left ventricular hypertrophy (in some patients);
Restrictive cardiomyopathy (in some patients);
Ventricular arrhythmia (in some patients)
MOLECULAR BASIS:
Caused by mutation in the actin, alpha, cardiac muscle gene (ACTC1,
102540.0001)
*FIELD* CD
Marla J. F. O'Neill: 6/16/2010
*FIELD* ED
joanna: 06/16/2010
*FIELD* CD
Marla J. F. O'Neill: 6/4/2010
*FIELD* ED
carol: 06/07/2010