Full text data of ACTA2
ACTA2
(ACTSA, ACTVS)
[Confidence: low (only semi-automatic identification from reviews)]
Actin, aortic smooth muscle (Alpha-actin-2; Cell growth-inhibiting gene 46 protein; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Actin, aortic smooth muscle (Alpha-actin-2; Cell growth-inhibiting gene 46 protein; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P62736
ID ACTA_HUMAN Reviewed; 377 AA.
AC P62736; B2R8A4; P03996; P04108; Q6FI19;
DT 23-OCT-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-AUG-2004, sequence version 1.
DT 22-JAN-2014, entry version 109.
DE RecName: Full=Actin, aortic smooth muscle;
DE AltName: Full=Alpha-actin-2;
DE AltName: Full=Cell growth-inhibiting gene 46 protein;
DE Flags: Precursor;
GN Name=ACTA2; Synonyms=ACTSA, ACTVS; ORFNames=GIG46;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2701935; DOI=10.1093/nar/17.4.1767;
RA Kamada S., Kakunaga T.;
RT "The nucleotide sequence of a human smooth muscle alpha-actin (aortic
RT type) cDNA.";
RL Nucleic Acids Res. 17:1767-1767(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2295650;
RA Reddy S., Ozgur K., Lu M., Chang W., Mohan S.R., Kumar C.C.,
RA Ruley H.E.;
RT "Structure of the human smooth muscle alpha-actin gene. Analysis of a
RT cDNA and 5' upstream region.";
RL J. Biol. Chem. 265:1683-1687(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kim J.W.;
RT "Identification of a human cell growth inhibiting gene.";
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-330.
RX PubMed=6330528;
RA Ueyama H., Hamada H., Battula N., Kakunaga T.;
RT "Structure of a human smooth muscle actin gene (aortic type) with a
RT unique intron site.";
RL Mol. Cell. Biol. 4:1073-1078(1984).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 331-377.
RX PubMed=2612915; DOI=10.1016/0378-1119(89)90520-9;
RA Kamada S., Nakano Y., Kakunaga T.;
RT "Structure of 3'-downstream segment of the human smooth muscle
RT (aortic-type) alpha-actin-encoding gene and isolation of the specific
RT DNA probe.";
RL Gene 84:455-462(1989).
RN [11]
RP INDUCTION, AND MASS SPECTROMETRY.
RX PubMed=16548883; DOI=10.1111/j.1462-5822.2005.00644.x;
RA Leong W.F., Chow V.T.;
RT "Transcriptomic and proteomic analyses of rhabdomyosarcoma cells
RT reveal differential cellular gene expression in response to
RT enterovirus 71 infection.";
RL Cell. Microbiol. 8:565-580(2006).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP VARIANTS AAT6 THR-117; GLN-118; HIS-135; CYS-149; ALA-154; CYS-258;
RP HIS-258; GLY-292 AND ASN-353.
RX PubMed=17994018; DOI=10.1038/ng.2007.6;
RA Guo D.-C., Pannu H., Tran-Fadulu V., Papke C.L., Yu R.K., Avidan N.,
RA Bourgeois S., Estrera A.L., Safi H.J., Sparks E., Amor D., Ades L.,
RA McConnell V., Willoughby C.E., Abuelo D., Willing M., Lewis R.A.,
RA Kim D.H., Scherer S., Tung P.P., Ahn C., Buja L.M., Raman C.S.,
RA Shete S.S., Milewicz D.M.;
RT "Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic
RT aortic aneurysms and dissections.";
RL Nat. Genet. 39:1488-1493(2007).
RN [14]
RP VARIANTS AAT6 HIS-39; THR-117; GLN-118; CYS-149; ALA-154; GLN-185;
RP GLN-212; HIS-258; CYS-258; ASN-326 AND ASN-353.
RX PubMed=19409525; DOI=10.1016/j.ajhg.2009.04.007;
RA Guo D.-C., Papke C.L., Tran-Fadulu V., Regalado E.S., Avidan N.,
RA Johnson R.J., Kim D.H., Pannu H., Willing M.C., Sparks E.,
RA Pyeritz R.E., Singh M.N., Dalman R.L., Grotta J.C., Marian A.J.,
RA Boerwinkle E.A., Frazier L.Q., LeMaire S.A., Coselli J.S.,
RA Estrera A.L., Safi H.J., Veeraraghavan S., Muzny D.M., Wheeler D.A.,
RA Willerson J.T., Yu R.K., Shete S.S., Scherer S.E., Raman C.S.,
RA Buja L.M., Milewicz D.M.;
RT "Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery
RT disease, stroke, and Moyamoya disease, along with thoracic aortic
RT disease.";
RL Am. J. Hum. Genet. 84:617-627(2009).
RN [15]
RP VARIANTS AAT6 CYS-145; CYS-149 AND GLN-212, AND PREDISPOSITION TO A
RP VARIETY OF VASCULAR DISEASES.
RX PubMed=19639654; DOI=10.1002/humu.21081;
RA Morisaki H., Akutsu K., Ogino H., Kondo N., Yamanaka I., Tsutsumi Y.,
RA Yoshimuta T., Okajima T., Matsuda H., Minatoya K., Sasaki H.,
RA Tanaka H., Ishibashi-Ueda H., Morisaki T.;
RT "Mutation of ACTA2 gene as an important cause of familial and
RT nonfamilial nonsyndromatic thoracic aortic aneurysm and/or dissection
RT (TAAD).";
RL Hum. Mutat. 30:1406-1411(2009).
RN [16]
RP VARIANT MSMDYS HIS-179.
RX PubMed=20734336; DOI=10.1002/ajmg.a.33657;
RA Milewicz D.M., Ostergaard J.R., Ala-Kokko L.M., Khan N., Grange D.K.,
RA Mendoza-Londono R., Bradley T.J., Olney A.H., Ades L., Maher J.F.,
RA Guo D., Buja L.M., Kim D., Hyland J.C., Regalado E.S.;
RT "De novo ACTA2 mutation causes a novel syndrome of multisystemic
RT smooth muscle dysfunction.";
RL Am. J. Med. Genet. A 152:2437-2443(2010).
RN [17]
RP VARIANT MYMY5 HIS-179.
RX PubMed=20970362; DOI=10.1016/j.ejpn.2010.09.002;
RA Roder C., Peters V., Kasuya H., Nishizawa T., Wakita S., Berg D.,
RA Schulte C., Khan N., Tatagiba M., Krischek B.;
RT "Analysis of ACTA2 in European Moyamoya disease patients.";
RL Eur. J. Paediatr. Neurol. 15:117-122(2011).
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 -!- INDUCTION: Up-regulated in response to enterovirus 71 (EV71)
CC infection.
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 (By similarity).
CC -!- DISEASE: Note=ACTA2 mutations predispose patients to a variety of
CC diffuse and diverse vascular diseases, premature onset coronary
CC artery disease (CAD), premature ischemic strokes and Moyamoya
CC disease.
CC -!- DISEASE: Aortic aneurysm, familial thoracic 6 (AAT6) [MIM:611788]:
CC A disease characterized by permanent dilation of the thoracic
CC aorta usually due to degenerative changes in the aortic wall. It
CC is primarily associated with a characteristic histologic
CC appearance known as 'medial necrosis' or 'Erdheim cystic medial
CC necrosis' in which there is degeneration and fragmentation of
CC elastic fibers, loss of smooth muscle cells, and an accumulation
CC of basophilic ground substance. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Moyamoya disease 5 (MYMY5) [MIM:614042]: A progressive
CC cerebral angiopathy characterized by bilateral intracranial
CC carotid artery stenosis and telangiectatic vessels in the region
CC of the basal ganglia. The abnormal vessels resemble a 'puff of
CC smoke' (moyamoya) on cerebral angiogram. Affected individuals can
CC develop transient ischemic attacks and/or cerebral infarction, and
CC rupture of the collateral vessels can cause intracranial
CC hemorrhage. Hemiplegia of sudden onset and epileptic seizures
CC constitute the prevailing presentation in childhood, while
CC subarachnoid bleeding occurs more frequently in adults. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Multisystemic smooth muscle dysfunction syndrome (MSMDYS)
CC [MIM:613834]: A syndrome characterized by dysfunction of smooth
CC muscle cells throughout the body, leading to aortic and
CC cerebrovascular disease, fixed dilated pupils, hypotonic bladder,
CC malrotation, and hypoperistalsis of the gut and pulmonary
CC hypertension. Note=The disease is caused by mutations affecting
CC the 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/ACTA2";
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DR EMBL; X13839; CAA32064.1; -; mRNA.
DR EMBL; J05192; AAA51577.1; -; mRNA.
DR EMBL; AY692464; AAW29811.1; -; mRNA.
DR EMBL; CR536518; CAG38756.1; -; mRNA.
DR EMBL; AK313294; BAG36101.1; -; mRNA.
DR EMBL; AL157394; CAI13864.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW50153.1; -; Genomic_DNA.
DR EMBL; BC017554; AAH17554.1; -; mRNA.
DR EMBL; BC093052; AAH93052.1; -; mRNA.
DR EMBL; K01741; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; K01742; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; K01743; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M33216; AAA60560.1; -; Genomic_DNA.
DR PIR; A35020; ATHUSM.
DR RefSeq; NP_001135417.1; NM_001141945.1.
DR RefSeq; NP_001604.1; NM_001613.2.
DR UniGene; Hs.500483; -.
DR ProteinModelPortal; P62736; -.
DR SMR; P62736; 4-377.
DR IntAct; P62736; 19.
DR STRING; 9606.ENSP00000224784; -.
DR PhosphoSite; P62736; -.
DR DMDM; 51316972; -.
DR REPRODUCTION-2DPAGE; IPI00008603; -.
DR UCD-2DPAGE; P62736; -.
DR PaxDb; P62736; -.
DR PRIDE; P62736; -.
DR DNASU; 59; -.
DR Ensembl; ENST00000224784; ENSP00000224784; ENSG00000107796.
DR Ensembl; ENST00000458208; ENSP00000402373; ENSG00000107796.
DR GeneID; 59; -.
DR KEGG; hsa:59; -.
DR UCSC; uc001kfp.3; human.
DR CTD; 59; -.
DR GeneCards; GC10M090684; -.
DR HGNC; HGNC:130; ACTA2.
DR HPA; CAB000002; -.
DR HPA; HPA041271; -.
DR MIM; 102620; gene.
DR MIM; 611788; phenotype.
DR MIM; 613834; phenotype.
DR MIM; 614042; phenotype.
DR neXtProt; NX_P62736; -.
DR Orphanet; 91387; Familial thoracic aortic aneurysm and aortic dissection.
DR Orphanet; 2573; Moyamoya disease.
DR PharmGKB; PA24456; -.
DR eggNOG; COG5277; -.
DR HOGENOM; HOG000233340; -.
DR HOVERGEN; HBG003771; -.
DR InParanoid; P62736; -.
DR KO; K12313; -.
DR OMA; AMCEEED; -.
DR OrthoDB; EOG72RMZ1; -.
DR PhylomeDB; P62736; -.
DR Reactome; REACT_17044; Muscle contraction.
DR SignaLink; P62736; -.
DR GeneWiki; ACTA2; -.
DR GenomeRNAi; 59; -.
DR NextBio; 249; -.
DR PMAP-CutDB; P62736; -.
DR PRO; PR:P62736; -.
DR ArrayExpress; P62736; -.
DR Bgee; P62736; -.
DR CleanEx; HS_ACTA2; -.
DR Genevestigator; P62736; -.
DR GO; GO:0015629; C:actin cytoskeleton; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043234; C:protein complex; IDA:MGI.
DR GO; GO:0030485; C:smooth muscle contractile fiber; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0072144; P:glomerular mesangial cell development; IEP:UniProtKB.
DR GO; GO:0006936; P:muscle contraction; TAS:Reactome.
DR GO; GO:0008217; P:regulation of blood pressure; IEA:Ensembl.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR GO; GO:0014829; P:vascular smooth muscle contraction; IEA:Ensembl.
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; Aortic aneurysm; ATP-binding; Complete proteome;
KW Cytoplasm; Cytoskeleton; Disease mutation; Methylation;
KW Muscle protein; Nucleotide-binding; Oxidation; Polymorphism;
KW Reference proteome.
FT PROPEP 1 2 Removed in mature form (By similarity).
FT /FTId=PRO_0000000738.
FT CHAIN 3 377 Actin, aortic smooth muscle.
FT /FTId=PRO_0000000739.
FT MOD_RES 3 3 N-acetylglutamate (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 VARIANT 39 39 R -> H (in AAT6).
FT /FTId=VAR_062577.
FT VARIANT 117 117 N -> T (in AAT6).
FT /FTId=VAR_045915.
FT VARIANT 118 118 R -> Q (in AAT6).
FT /FTId=VAR_045916.
FT VARIANT 135 135 Y -> H (in AAT6).
FT /FTId=VAR_045917.
FT VARIANT 145 145 Y -> C (in AAT6).
FT /FTId=VAR_062578.
FT VARIANT 149 149 R -> C (in AAT6).
FT /FTId=VAR_045918.
FT VARIANT 154 154 V -> A (in AAT6).
FT /FTId=VAR_045919.
FT VARIANT 179 179 R -> H (in MYMY5 and MSMDYS; disease
FT phenotype include smooth muscle cells
FT dysfunction in organs throughout the body
FT with decreased contractile function in
FT the iris, bladder and gastrointestinal
FT tract).
FT /FTId=VAR_064516.
FT VARIANT 185 185 R -> Q (in AAT6).
FT /FTId=VAR_062579.
FT VARIANT 196 196 T -> S (in dbSNP:rs1803028).
FT /FTId=VAR_011944.
FT VARIANT 212 212 R -> Q (in AAT6).
FT /FTId=VAR_062580.
FT VARIANT 258 258 R -> C (in AAT6).
FT /FTId=VAR_045920.
FT VARIANT 258 258 R -> H (in AAT6).
FT /FTId=VAR_045921.
FT VARIANT 292 292 R -> G (in AAT6).
FT /FTId=VAR_045922.
FT VARIANT 320 320 T -> A (in dbSNP:rs1803027).
FT /FTId=VAR_011945.
FT VARIANT 326 326 T -> N (in AAT6).
FT /FTId=VAR_062581.
FT VARIANT 353 353 T -> N (in AAT6).
FT /FTId=VAR_045923.
FT VARIANT 373 373 H -> P (in dbSNP:rs1062398).
FT /FTId=VAR_011946.
FT CONFLICT 234 234 S -> W (in Ref. 2; AAA51577).
SQ SEQUENCE 377 AA; 42009 MW; 2D0543262DB35CA5 CRC64;
MCEEEDSTAL VCDNGSGLCK AGFAGDDAPR AVFPSIVGRP RHQGVMVGMG QKDSYVGDEA
QSKRGILTLK YPIEHGIITN WDDMEKIWHH SFYNELRVAP 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 ACTA_HUMAN Reviewed; 377 AA.
AC P62736; B2R8A4; P03996; P04108; Q6FI19;
DT 23-OCT-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-AUG-2004, sequence version 1.
DT 22-JAN-2014, entry version 109.
DE RecName: Full=Actin, aortic smooth muscle;
DE AltName: Full=Alpha-actin-2;
DE AltName: Full=Cell growth-inhibiting gene 46 protein;
DE Flags: Precursor;
GN Name=ACTA2; Synonyms=ACTSA, ACTVS; ORFNames=GIG46;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2701935; DOI=10.1093/nar/17.4.1767;
RA Kamada S., Kakunaga T.;
RT "The nucleotide sequence of a human smooth muscle alpha-actin (aortic
RT type) cDNA.";
RL Nucleic Acids Res. 17:1767-1767(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2295650;
RA Reddy S., Ozgur K., Lu M., Chang W., Mohan S.R., Kumar C.C.,
RA Ruley H.E.;
RT "Structure of the human smooth muscle alpha-actin gene. Analysis of a
RT cDNA and 5' upstream region.";
RL J. Biol. Chem. 265:1683-1687(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kim J.W.;
RT "Identification of a human cell growth inhibiting gene.";
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-330.
RX PubMed=6330528;
RA Ueyama H., Hamada H., Battula N., Kakunaga T.;
RT "Structure of a human smooth muscle actin gene (aortic type) with a
RT unique intron site.";
RL Mol. Cell. Biol. 4:1073-1078(1984).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 331-377.
RX PubMed=2612915; DOI=10.1016/0378-1119(89)90520-9;
RA Kamada S., Nakano Y., Kakunaga T.;
RT "Structure of 3'-downstream segment of the human smooth muscle
RT (aortic-type) alpha-actin-encoding gene and isolation of the specific
RT DNA probe.";
RL Gene 84:455-462(1989).
RN [11]
RP INDUCTION, AND MASS SPECTROMETRY.
RX PubMed=16548883; DOI=10.1111/j.1462-5822.2005.00644.x;
RA Leong W.F., Chow V.T.;
RT "Transcriptomic and proteomic analyses of rhabdomyosarcoma cells
RT reveal differential cellular gene expression in response to
RT enterovirus 71 infection.";
RL Cell. Microbiol. 8:565-580(2006).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP VARIANTS AAT6 THR-117; GLN-118; HIS-135; CYS-149; ALA-154; CYS-258;
RP HIS-258; GLY-292 AND ASN-353.
RX PubMed=17994018; DOI=10.1038/ng.2007.6;
RA Guo D.-C., Pannu H., Tran-Fadulu V., Papke C.L., Yu R.K., Avidan N.,
RA Bourgeois S., Estrera A.L., Safi H.J., Sparks E., Amor D., Ades L.,
RA McConnell V., Willoughby C.E., Abuelo D., Willing M., Lewis R.A.,
RA Kim D.H., Scherer S., Tung P.P., Ahn C., Buja L.M., Raman C.S.,
RA Shete S.S., Milewicz D.M.;
RT "Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic
RT aortic aneurysms and dissections.";
RL Nat. Genet. 39:1488-1493(2007).
RN [14]
RP VARIANTS AAT6 HIS-39; THR-117; GLN-118; CYS-149; ALA-154; GLN-185;
RP GLN-212; HIS-258; CYS-258; ASN-326 AND ASN-353.
RX PubMed=19409525; DOI=10.1016/j.ajhg.2009.04.007;
RA Guo D.-C., Papke C.L., Tran-Fadulu V., Regalado E.S., Avidan N.,
RA Johnson R.J., Kim D.H., Pannu H., Willing M.C., Sparks E.,
RA Pyeritz R.E., Singh M.N., Dalman R.L., Grotta J.C., Marian A.J.,
RA Boerwinkle E.A., Frazier L.Q., LeMaire S.A., Coselli J.S.,
RA Estrera A.L., Safi H.J., Veeraraghavan S., Muzny D.M., Wheeler D.A.,
RA Willerson J.T., Yu R.K., Shete S.S., Scherer S.E., Raman C.S.,
RA Buja L.M., Milewicz D.M.;
RT "Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery
RT disease, stroke, and Moyamoya disease, along with thoracic aortic
RT disease.";
RL Am. J. Hum. Genet. 84:617-627(2009).
RN [15]
RP VARIANTS AAT6 CYS-145; CYS-149 AND GLN-212, AND PREDISPOSITION TO A
RP VARIETY OF VASCULAR DISEASES.
RX PubMed=19639654; DOI=10.1002/humu.21081;
RA Morisaki H., Akutsu K., Ogino H., Kondo N., Yamanaka I., Tsutsumi Y.,
RA Yoshimuta T., Okajima T., Matsuda H., Minatoya K., Sasaki H.,
RA Tanaka H., Ishibashi-Ueda H., Morisaki T.;
RT "Mutation of ACTA2 gene as an important cause of familial and
RT nonfamilial nonsyndromatic thoracic aortic aneurysm and/or dissection
RT (TAAD).";
RL Hum. Mutat. 30:1406-1411(2009).
RN [16]
RP VARIANT MSMDYS HIS-179.
RX PubMed=20734336; DOI=10.1002/ajmg.a.33657;
RA Milewicz D.M., Ostergaard J.R., Ala-Kokko L.M., Khan N., Grange D.K.,
RA Mendoza-Londono R., Bradley T.J., Olney A.H., Ades L., Maher J.F.,
RA Guo D., Buja L.M., Kim D., Hyland J.C., Regalado E.S.;
RT "De novo ACTA2 mutation causes a novel syndrome of multisystemic
RT smooth muscle dysfunction.";
RL Am. J. Med. Genet. A 152:2437-2443(2010).
RN [17]
RP VARIANT MYMY5 HIS-179.
RX PubMed=20970362; DOI=10.1016/j.ejpn.2010.09.002;
RA Roder C., Peters V., Kasuya H., Nishizawa T., Wakita S., Berg D.,
RA Schulte C., Khan N., Tatagiba M., Krischek B.;
RT "Analysis of ACTA2 in European Moyamoya disease patients.";
RL Eur. J. Paediatr. Neurol. 15:117-122(2011).
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 -!- INDUCTION: Up-regulated in response to enterovirus 71 (EV71)
CC infection.
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 (By similarity).
CC -!- DISEASE: Note=ACTA2 mutations predispose patients to a variety of
CC diffuse and diverse vascular diseases, premature onset coronary
CC artery disease (CAD), premature ischemic strokes and Moyamoya
CC disease.
CC -!- DISEASE: Aortic aneurysm, familial thoracic 6 (AAT6) [MIM:611788]:
CC A disease characterized by permanent dilation of the thoracic
CC aorta usually due to degenerative changes in the aortic wall. It
CC is primarily associated with a characteristic histologic
CC appearance known as 'medial necrosis' or 'Erdheim cystic medial
CC necrosis' in which there is degeneration and fragmentation of
CC elastic fibers, loss of smooth muscle cells, and an accumulation
CC of basophilic ground substance. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Moyamoya disease 5 (MYMY5) [MIM:614042]: A progressive
CC cerebral angiopathy characterized by bilateral intracranial
CC carotid artery stenosis and telangiectatic vessels in the region
CC of the basal ganglia. The abnormal vessels resemble a 'puff of
CC smoke' (moyamoya) on cerebral angiogram. Affected individuals can
CC develop transient ischemic attacks and/or cerebral infarction, and
CC rupture of the collateral vessels can cause intracranial
CC hemorrhage. Hemiplegia of sudden onset and epileptic seizures
CC constitute the prevailing presentation in childhood, while
CC subarachnoid bleeding occurs more frequently in adults. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Multisystemic smooth muscle dysfunction syndrome (MSMDYS)
CC [MIM:613834]: A syndrome characterized by dysfunction of smooth
CC muscle cells throughout the body, leading to aortic and
CC cerebrovascular disease, fixed dilated pupils, hypotonic bladder,
CC malrotation, and hypoperistalsis of the gut and pulmonary
CC hypertension. Note=The disease is caused by mutations affecting
CC the 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/ACTA2";
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DR EMBL; X13839; CAA32064.1; -; mRNA.
DR EMBL; J05192; AAA51577.1; -; mRNA.
DR EMBL; AY692464; AAW29811.1; -; mRNA.
DR EMBL; CR536518; CAG38756.1; -; mRNA.
DR EMBL; AK313294; BAG36101.1; -; mRNA.
DR EMBL; AL157394; CAI13864.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW50153.1; -; Genomic_DNA.
DR EMBL; BC017554; AAH17554.1; -; mRNA.
DR EMBL; BC093052; AAH93052.1; -; mRNA.
DR EMBL; K01741; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; K01742; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; K01743; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M33216; AAA60560.1; -; Genomic_DNA.
DR PIR; A35020; ATHUSM.
DR RefSeq; NP_001135417.1; NM_001141945.1.
DR RefSeq; NP_001604.1; NM_001613.2.
DR UniGene; Hs.500483; -.
DR ProteinModelPortal; P62736; -.
DR SMR; P62736; 4-377.
DR IntAct; P62736; 19.
DR STRING; 9606.ENSP00000224784; -.
DR PhosphoSite; P62736; -.
DR DMDM; 51316972; -.
DR REPRODUCTION-2DPAGE; IPI00008603; -.
DR UCD-2DPAGE; P62736; -.
DR PaxDb; P62736; -.
DR PRIDE; P62736; -.
DR DNASU; 59; -.
DR Ensembl; ENST00000224784; ENSP00000224784; ENSG00000107796.
DR Ensembl; ENST00000458208; ENSP00000402373; ENSG00000107796.
DR GeneID; 59; -.
DR KEGG; hsa:59; -.
DR UCSC; uc001kfp.3; human.
DR CTD; 59; -.
DR GeneCards; GC10M090684; -.
DR HGNC; HGNC:130; ACTA2.
DR HPA; CAB000002; -.
DR HPA; HPA041271; -.
DR MIM; 102620; gene.
DR MIM; 611788; phenotype.
DR MIM; 613834; phenotype.
DR MIM; 614042; phenotype.
DR neXtProt; NX_P62736; -.
DR Orphanet; 91387; Familial thoracic aortic aneurysm and aortic dissection.
DR Orphanet; 2573; Moyamoya disease.
DR PharmGKB; PA24456; -.
DR eggNOG; COG5277; -.
DR HOGENOM; HOG000233340; -.
DR HOVERGEN; HBG003771; -.
DR InParanoid; P62736; -.
DR KO; K12313; -.
DR OMA; AMCEEED; -.
DR OrthoDB; EOG72RMZ1; -.
DR PhylomeDB; P62736; -.
DR Reactome; REACT_17044; Muscle contraction.
DR SignaLink; P62736; -.
DR GeneWiki; ACTA2; -.
DR GenomeRNAi; 59; -.
DR NextBio; 249; -.
DR PMAP-CutDB; P62736; -.
DR PRO; PR:P62736; -.
DR ArrayExpress; P62736; -.
DR Bgee; P62736; -.
DR CleanEx; HS_ACTA2; -.
DR Genevestigator; P62736; -.
DR GO; GO:0015629; C:actin cytoskeleton; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043234; C:protein complex; IDA:MGI.
DR GO; GO:0030485; C:smooth muscle contractile fiber; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0072144; P:glomerular mesangial cell development; IEP:UniProtKB.
DR GO; GO:0006936; P:muscle contraction; TAS:Reactome.
DR GO; GO:0008217; P:regulation of blood pressure; IEA:Ensembl.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR GO; GO:0014829; P:vascular smooth muscle contraction; IEA:Ensembl.
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; Aortic aneurysm; ATP-binding; Complete proteome;
KW Cytoplasm; Cytoskeleton; Disease mutation; Methylation;
KW Muscle protein; Nucleotide-binding; Oxidation; Polymorphism;
KW Reference proteome.
FT PROPEP 1 2 Removed in mature form (By similarity).
FT /FTId=PRO_0000000738.
FT CHAIN 3 377 Actin, aortic smooth muscle.
FT /FTId=PRO_0000000739.
FT MOD_RES 3 3 N-acetylglutamate (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 VARIANT 39 39 R -> H (in AAT6).
FT /FTId=VAR_062577.
FT VARIANT 117 117 N -> T (in AAT6).
FT /FTId=VAR_045915.
FT VARIANT 118 118 R -> Q (in AAT6).
FT /FTId=VAR_045916.
FT VARIANT 135 135 Y -> H (in AAT6).
FT /FTId=VAR_045917.
FT VARIANT 145 145 Y -> C (in AAT6).
FT /FTId=VAR_062578.
FT VARIANT 149 149 R -> C (in AAT6).
FT /FTId=VAR_045918.
FT VARIANT 154 154 V -> A (in AAT6).
FT /FTId=VAR_045919.
FT VARIANT 179 179 R -> H (in MYMY5 and MSMDYS; disease
FT phenotype include smooth muscle cells
FT dysfunction in organs throughout the body
FT with decreased contractile function in
FT the iris, bladder and gastrointestinal
FT tract).
FT /FTId=VAR_064516.
FT VARIANT 185 185 R -> Q (in AAT6).
FT /FTId=VAR_062579.
FT VARIANT 196 196 T -> S (in dbSNP:rs1803028).
FT /FTId=VAR_011944.
FT VARIANT 212 212 R -> Q (in AAT6).
FT /FTId=VAR_062580.
FT VARIANT 258 258 R -> C (in AAT6).
FT /FTId=VAR_045920.
FT VARIANT 258 258 R -> H (in AAT6).
FT /FTId=VAR_045921.
FT VARIANT 292 292 R -> G (in AAT6).
FT /FTId=VAR_045922.
FT VARIANT 320 320 T -> A (in dbSNP:rs1803027).
FT /FTId=VAR_011945.
FT VARIANT 326 326 T -> N (in AAT6).
FT /FTId=VAR_062581.
FT VARIANT 353 353 T -> N (in AAT6).
FT /FTId=VAR_045923.
FT VARIANT 373 373 H -> P (in dbSNP:rs1062398).
FT /FTId=VAR_011946.
FT CONFLICT 234 234 S -> W (in Ref. 2; AAA51577).
SQ SEQUENCE 377 AA; 42009 MW; 2D0543262DB35CA5 CRC64;
MCEEEDSTAL VCDNGSGLCK AGFAGDDAPR AVFPSIVGRP RHQGVMVGMG QKDSYVGDEA
QSKRGILTLK YPIEHGIITN WDDMEKIWHH SFYNELRVAP 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
102620
*RECORD*
*FIELD* NO
102620
*FIELD* TI
*102620 ACTIN, ALPHA-2, SMOOTH MUSCLE, AORTA; ACTA2
;;ACTIN, ALPHA, SMOOTH MUSCLE, AORTIC; ACTSA;;
read moreACTIN, VASCULAR SMOOTH MUSCLE
*FIELD* TX
DESCRIPTION
Smooth muscle aortic alpha-actin (ACTA2) is 1 of 6 different actin
isoforms that have been identified in vertebrates and that share similar
amino acid sequences and are well conserved in evolution. Other actins
include skeletal muscle (ACTA1; 102610), cardiac muscle (ACTC1; 102540)
, smooth muscle enteric (ACTG2; 102545), and cytoplasmic beta (ACTB;
102630) and gamma (ACTG1; 102560) (summary by Vandekerckhove and Weber,
1979).
CLONING
Ueyama et al. (1984) isolated and characterized the ACTA2 gene, encoding
smooth muscle aortic actin. The gene has a transition point mutation in
position 309, substituting thymine for cytosine.
GENE STRUCTURE
Ueyama et al. (1984) found that the ACTA2 gene contains at least 9
exons.
MAPPING
Ueyama et al. (1990) assigned the ACTSA gene to chromosome 10 by
Southern blot analysis of DNAs from 18 rodent-human somatic cell
hybrids. Regional mapping by in situ hybridization localized the gene to
chromosome 10q22-q24.
By FISH analysis, Ueyama et al. (1995) localized the ACTA2 gene to
chromosome 10q23.3.
GENE FUNCTION
Kumar et al. (2003) developed transgenic mice expressing a reporter
construct driven by the rat Actsa promoter. Mutation of 1 or both E
boxes within the promoter significantly reduced expression of the
reporter gene. Mouse fibroblasts cotransfected with the reporter plasmid
and various transcription factors revealed that serum response factor
(SRF; 600589), class I bHLH proteins, such as E12 (147141), HEB
(600480), and E2-2 (602272), and the bHLH inhibitors ID (see ID1;
600349) and TWIST (601622) are likely important regulators of smooth
muscle cell differentiation.
MOLECULAR GENETICS
The major function of vascular smooth muscle cells (SMCs) is contraction
to regulate blood pressure and flow. SMC contractile force requires
cyclic interactions between SMC alpha-actin, encoded by ACTA2, and the
beta-myosin heavy chain, encoded by the MYH11 gene (160745). Guo et al.
(2007) showed that missense mutations in ACTA2 are responsible for 14%
of inherited ascending thoracic aortic aneurysms and dissections (AAT6;
611788). Structural analyses and immunofluorescence of actin filaments
in SMCs derived from individuals heterozygous for ACTA2 mutations
illustrated that these mutations interfere with actin filament assembly
and are predicted to decrease SMC contraction. Aortic tissues from
affected individuals showed aortic medial degeneration, focal areas of
medial SMC hyperplasia and disarray, and stenotic arteries in the vasa
vasorum due to medial SMC proliferation. These data, along with the
previously reported MYH11 mutations causing familial thoracic aortic
aneurysm, indicate the importance of SMC contraction in maintaining the
structural integrity of the ascending aorta. Since mutations in 2
components of the SMC contractile unit, ACTA2 and MYH11, cause familial
thoracic aortic aneurysm with dissection (TAAD), Guo et al. (2007)
raised the possibility that mutations in other components of the SMC
contractile unit may be responsible for a portion of the 80% of familial
TAAD yet to be explained.
Guo et al. (2007) found that the penetrance of TAAD in individuals with
ACTA2 mutations was low (0.48) and did not increase with age, differing
from the pattern for other identified loci and genes for familial TAAD,
which have a higher, age-related penetrance. Despite the young age of
death of some family members, the Kaplan-Meier survival curve of the
ACTA2 cohort estimated a median survival of 67 years, suggesting that
the disease is less deadly than Loeys-Dietz syndrome (609192) and
similar to treated Marfan syndrome (MFS; 154700).
Guo et al. (2009) studied 20 families with 127 members harboring
heterozygous ACTA2 mutations and phenotyped them for premature vascular
disease, defined as an age of onset less than 55 years in men and less
than 60 years in women. Family members aged 21 years and older were
included, along with members who presented with vascular diseases at
younger ages. Thoracic aortic aneurysm had been reported in 14 of these
20 families by Guo et al. (2007). The 6 additional families with ACTA2
mutations all carried missense mutations. None of these missense
mutations was identified in 192 ethnically matched controls. Thoracic
aortic aneurysm was the primary vascular disease in ACTA2 mutation
carriers (76 individuals); 26 individuals had premature onset of
coronary artery disease, and 15 had ischemic strokes. Fifteen
individuals had more than 1 vascular disease, and none of the family
members without an ACTA2 mutation had any of these early-onset vascular
diseases. One family had more mutation carriers with premature coronary
artery disease than with aortic disease. In 3 families with an ACTA2
mutation altering the arginine-258 residue (arg258 to cys, 102620.0003,
arg258 to his, 102620.0002), 10 of 14 mutation carriers had aortic
disease and 7 had onset of strokes at ages ranging from 5 to 46 years.
Five of the 7 acute strokes had been classified as moyamoya disease
(MYMY5; 614042); 2 others had fusiform cerebral aneurysms.
Shimojima and Yamamoto (2009) analyzed all coding exons of the ACTA2
gene in 53 Japanese patients with moyamoya disease but found no
mutations. Noting that the diagnosis of moyamoya disease in the patients
studied by Guo et al. (2009) was unclear, Shimojima and Yamamoto (2009)
concluded that ACTA2 is not a major disease-causing gene for moyamoya
disease in Japanese patients.
Milewicz et al. (2010) identified 7 unrelated patients with a de novo
missense mutation in the ACTA2 gene (102620.0004) who presented with a
multisystemic smooth muscle dysfunction syndrome (613834), including
vasculopathy, congenital mydriasis, patent ductus arteriosus, and
thoracic aortic aneurysm.
Roder et al. (2011) identified a heterozygous mutation in the ACTA2 gene
(R179H; 102620.0004) in 1 of 39 unrelated patients of European descent
with moyamoya disease who had no family history of the disorder. No
other previously described ACTA2 mutations associated with moyamoya
disease (Guo et al., 2009) were found in this cohort.
In 40 German probands with thoracic aortic aneurysms, 21 of whom had
clinical features suggestive of Marfan syndrome, but all of whom were
negative for mutation in the FBN1 (134797) and TGFBR2 (190182) genes,
Hoffjan et al. (2011) sequenced the ACTA2 gene and identified
heterozygous mutations in 3 patients (see, e.g., 102620.0005 and
102620.0006). None of the 21 individuals with features suggestive of MFS
were found to carry a mutation in ACTA2. Among the remaining 19
patients, there were no differences between the 3 patients with ACTA2
mutations and the nonmutated patients. The authors also noted that there
was no history of premature stroke or coronary artery disease in the
mutation-positive families.
*FIELD* AV
.0001
AORTIC ANEURYSM, FAMILIAL THORACIC 6
ACTA2, ARG149CYS
In a large family in which thoracic aortic aneurysm with dissection
segregated with reduced penetrance (AAT6; 611788), Guo et al. (2007)
found a heterozygous 492C-T transition in exon 5 of the ACTA2 gene that
caused an arg149-to-cys (R149C) amino acid substitution. In further
studies, 4 additional families with the ACTA2 mutation were found;
however, each family had a unique haplotype, implying that the mutations
arose de novo in multiple families. Livedo reticularis and iris flocculi
were found together or separately in some of these families.
Guo et al. (2009) analyzed 45 individuals with the R149C mutation and
found that, in addition to the already established predisposition to
TAAD, this mutation led to coronary artery disease (24 mutation carriers
with TAAD, 12 with coronary artery disease).
.0002
AORTIC ANEURYSM, FAMILIAL THORACIC 6
MOYAMOYA DISEASE 5, INCLUDED
ACTA2, ARG258HIS
In a family of European descent with hereditary thoracic aortic aneurysm
with dissection (AAT6; 611788), Guo et al. (2007) identified an 820G-A
transition in exon 7 of the ACTA2 gene, resulting in an arg258-to-his
(R258H) substitution. One individual in the family had patent ductus
arteriosus.
Guo et al. (2009) analyzed 15 individuals carrying a missense mutation
at arg258 and found that, in addition to the already established
predisposition to TAAD, mutation at this position was associated with
stroke (10 individuals with TAAD, 7 with stroke). In 1 family with the
R258H mutation, 3 affected individuals had a phenotype consistent with
moyamoya disease-5 (MYMY5; 614042). Two of these 3 patients had strokes
at ages 44 and 46 years, respectively, and also had thoracic aortic
aneurysm with dissection; the third had isolated moyamoya disease with
stroke at age 16 years. The findings indicated that ACTA2 mutations can
cause a spectrum of vascular diseases, even within a single family.
.0003
AORTIC ANEURYSM, FAMILIAL THORACIC 6
MOYAMOYA DISEASE 5, INCLUDED
ACTA2, ARG258CYS
In 2 families of European descent with hereditary thoracic aortic
aneurysm with dissection (AAT6; 611788), Guo et al. (2007) identified an
819C-T transition in exon 7 of the ACTA2 gene, resulting in an
arg258-to-cys (R258C) substitution. All 5 mutation carriers in 1 family
had patent ductus arteriosus.
Guo et al. (2009) analyzed 15 individuals carrying a missense mutation
at arg258 and found that, in addition to the already established
predisposition to TAAD, mutation at this position was associated with
stroke (10 individuals with TAAD, 7 with stroke). The authors identified
a high risk of early-onset strokes in family members carrying the R258C
mutation. In 1 family with the R258C mutation, 2 members had a phenotype
consistent with moyamoya disease-5 (614042), with strokes at ages 39 and
5 years, respectively. The older patient had thoracic aneurysm with
dissection at age 32 years, whereas the stroke was fatal in the younger
patient. The findings indicated that ACTA2 mutations can cause a
spectrum of vascular diseases, even within a single family.
.0004
MULTISYSTEMIC SMOOTH MUSCLE DYSFUNCTION SYNDROME
MOYAMOYA DISEASE 5, INCLUDED
ACTA2, ARG179HIS
In 7 unrelated patients of northern European descent with multisystemic
smooth muscle dysfunction syndrome (613834), Milewicz et al. (2010)
identified heterozygosity for a de novo arg179-to-his (R179H)
substitution in the ACTA2 gene. The mutation was not identified in
parents' DNA samples, confirming the de novo status in 5 patients. Three
of the patients had been previously reported (Ades et al., 1999, Kahn et
al., 2004, and Lemire et al., 2004, respectively).
Roder et al. (2011) identified a heterozygous R179H mutation in 1 of 39
patients of European origin with moyamoya disease-5 (614042) and no
family history of the disorder. The patient was a girl who had a stroke
at age 3 years, but she had no other abnormalities, particularly none of
those described by Milewicz et al. (2010).
.0005
AORTIC ANEURYSM, FAMILIAL THORACIC 6
ACTA2, ARG39CYS
In a 3-generation German family with autosomal dominant thoracic aortic
aneurysm (AAT6; 611788), Hoffjan et al. (2011) identified heterozygosity
for a c.115C-T transition in exon 2 of the ACTA2 gene, resulting in an
arg39-to-cys (R39C) substitution at a highly conserved residue adjacent
to the DNAse-I-binding loop within subdomain 2. The mutation segregated
with disease in the family and was not found in 192 control chromosomes
or in the GenBank dbSNP library. The vascular phenotype was variable in
this family, ranging from mild aortic dilation and insufficiency in a
44-year-old woman to overt aortic aneurysm extending from the ascending
to the abdominal aorta in a 25-year-old man. None of the affected
individuals showed syndromic features, and there was no history of
premature stroke or coronary artery disease. Hoffjan et al. (2011) noted
that although a different mutation at the R39 residue, R39H, had been
associated with type A dissections in 2 families and with type B
dissections in another family (Guo et al., 2009), dissections were not
observed in the family with the R39C mutation.
.0006
AORTIC ANEURYSM, FAMILIAL THORACIC 6
ACTA2, MET49VAL
In a German woman who presented with acute aortic dissection at 37 years
of age, Hoffjan et al. (2011) identified heterozygosity for a c.145A-G
transition in exon 3 of the ACTA2 gene, resulting in a met49-to-val
(M49V) substitution at a highly conserved residue in the DNAse-I-binding
loop within subdomain 2. The mutation was not found in 192 control
chromosomes or in the GenBank dbSNP library. The patient's brother had
died at 29 years of age from acute aortic dissection, and her mother,
who suffered from slowly progressive spastic paraplegia over 20 years
and cancer, died suddenly at 69 years of age in association with a
massive drop in blood pressure.
*FIELD* RF
1. Ades, L. C.; Davies, R.; Haan, E. A.; Holman, K. J.; Watson, K.
C.; Sreetharan, D.; Cao, S. N.; Milewicz, D. M.; Bateman, J. F.; Chiodo,
A. A.; Eccles, M.; McNoe, L.; Harbord, M.: Aortic dissection, patent
ductus arteriosus, iris hypoplasia and brachytelephalangy in a male
adolescent. Clin. Dysmorph. 8: 269-276, 1999.
2. Guo, D.-C.; Pannu, H.; Tran-Fadulu, V.; Papke, C. L.; Yu, R. K.;
Avidan, N.; Bourgeois, S.; Estrera, A. L.; Safi, H. J.; Sparks, E.;
Amor, D.; Ades, L.; and 13 others: Mutations in smooth muscle alpha-actin
(ACTA2) lead to thoracic aortic aneurysms and dissections. Nature
Genet. 39: 1488-1493, 2007. Note: Erratum: Nature Genet. 40: 255
only, 2008.
3. Guo, D.-C.; Papke, C. L.; Tran-Fadulu, V.; Regalado, E. S.; Avidan,
N.; Johnson, R. J.; Kim, D. H.; Pannu, H.; Willing, M. C.; Sparks,
E.; Pyeritz, R. E.; Singh, M. N.; and 19 others: Mutations in smooth
muscle alpha-actin (ACTA2) cause coronary artery disease, stroke,
and Moyamoya disease, along with thoracic aortic disease. Am. J.
Hum. Genet. 84: 617-627, 2009.
4. Hoffjan, S.; Waldmuller, S.; Blankenfeldt, W.; Kotting, J.; Gehle,
P.; Binner, P.; Epplen, J. T.; Scheffold, T.: Three novel mutations
in the ACTA2 gene in German patients with thoracic aortic aneurysms
and dissections. Europ. J. Hum. Genet. 19: 520-524, 2011.
5. Kahn, N.; Schinzel, A.; Shuknecht, B.; Baumann, F.; Ostergaard,
J. R.; Yonekawa, Y.: Moyamoya angiopathy with dolichoectatic internal
carotid arteries, patent ductus arteriosus and pupillary dysfunction:
a new genetic syndrome? Europ. Neurol. 51: 72-77, 2004.
6. Kumar, M. S.; Hendrix, J. A.; Johnson, A. D.; Owens, G. K.: Smooth
muscle alpha-actin gene requires two E-boxes for proper expression
in vivo and is a target of class I basic helix-loop-helix proteins. Circ.
Res. 92: 840-847, 2003.
7. Lemire, B. D.; Buncic, J. R.; Kennedy, S. J.; Dyack, S. J.; Teebi,
A. S.: Congenital mydriasis, patent ductus arteriosus, and congenital
cystic lung disease: new syndromic spectrum? Am. J. Med. Genet. 131:
318-319, 2004.
8. Milewicz, D. M.; Ostergaard, J. R.; Ala-Kokko, L. M.; Khan, N.;
Grange, D. K.; Mendoza-Londono, R.; Bradley, T. J.; Olney, A. H.;
Ades, L.; Maher, J. F.; Guo, D.; Buja, L. M.; Kim, D.; Hyland, J.
C.; Regalado, E. S.: De novo ACTA2 mutation causes a novel syndrome
of multisystemic smooth muscle dysfunction. Am. J. Med. Genet. 152A:
2437-2443, 2010.
9. Roder, C.; Peters, V.; Kasuya, H.; Nishizawa, T.; Wakita, S.; Berg,
D.; Schulte, C.; Khan, N.; Tatagiba, M.; Krischek, B.: Analysis of
ACTA2 in European Moyamoya disease patients. Europ. J. Paediat. Neurol. 15:
117-122, 2011.
10. Shimojima, K.; Yamamoto, T.: ACTA2 is not a major disease-causing
gene for moyamoya disease. (Letter) J. Hum. Genet. 54: 687-688,
2009.
11. Ueyama, H.; Bruns, G.; Kanda, N.: Assignment of the vascular
smooth muscle actin gene ACTSA to human chromosome 10. Jinrui Idengaku
Zasshi 35: 145-150, 1990.
12. Ueyama, H.; Hamada, H.; Battula, N.; Kakunaga, T.: Structure
of a human smooth muscle actin gene (aortic type) with a unique intron
site. Molec. Cell. Biol. 4: 1073-1078, 1984.
13. 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.
14. Vandekerckhove, J.; Weber, K.: The complete amino acid sequence
of actins from bovine aorta, bovine heart, bovine fast skeletal muscle,
and rabbit slow skeletal muscle. Differentiation 14: 123-133, 1979.
*FIELD* CN
Marla J. F. O'Neill - updated: 09/24/2013
Cassandra L. Kniffin - updated: 6/14/2011
Ada Hamosh - updated: 3/24/2011
Ada Hamosh - updated: 10/6/2009
Victor A. McKusick - updated: 12/20/2007
Patricia A. Hartz - updated: 3/24/2004
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 09/24/2013
carol: 5/30/2012
wwang: 6/27/2011
ckniffin: 6/14/2011
terry: 4/25/2011
wwang: 3/25/2011
terry: 3/24/2011
wwang: 6/11/2010
alopez: 10/12/2009
terry: 10/6/2009
carol: 12/10/2008
alopez: 6/24/2008
terry: 12/20/2007
mgross: 4/14/2004
terry: 3/24/2004
terry: 6/16/1995
supermim: 3/16/1992
carol: 2/27/1992
carol: 7/3/1991
carol: 3/19/1991
carol: 9/27/1990
*RECORD*
*FIELD* NO
102620
*FIELD* TI
*102620 ACTIN, ALPHA-2, SMOOTH MUSCLE, AORTA; ACTA2
;;ACTIN, ALPHA, SMOOTH MUSCLE, AORTIC; ACTSA;;
read moreACTIN, VASCULAR SMOOTH MUSCLE
*FIELD* TX
DESCRIPTION
Smooth muscle aortic alpha-actin (ACTA2) is 1 of 6 different actin
isoforms that have been identified in vertebrates and that share similar
amino acid sequences and are well conserved in evolution. Other actins
include skeletal muscle (ACTA1; 102610), cardiac muscle (ACTC1; 102540)
, smooth muscle enteric (ACTG2; 102545), and cytoplasmic beta (ACTB;
102630) and gamma (ACTG1; 102560) (summary by Vandekerckhove and Weber,
1979).
CLONING
Ueyama et al. (1984) isolated and characterized the ACTA2 gene, encoding
smooth muscle aortic actin. The gene has a transition point mutation in
position 309, substituting thymine for cytosine.
GENE STRUCTURE
Ueyama et al. (1984) found that the ACTA2 gene contains at least 9
exons.
MAPPING
Ueyama et al. (1990) assigned the ACTSA gene to chromosome 10 by
Southern blot analysis of DNAs from 18 rodent-human somatic cell
hybrids. Regional mapping by in situ hybridization localized the gene to
chromosome 10q22-q24.
By FISH analysis, Ueyama et al. (1995) localized the ACTA2 gene to
chromosome 10q23.3.
GENE FUNCTION
Kumar et al. (2003) developed transgenic mice expressing a reporter
construct driven by the rat Actsa promoter. Mutation of 1 or both E
boxes within the promoter significantly reduced expression of the
reporter gene. Mouse fibroblasts cotransfected with the reporter plasmid
and various transcription factors revealed that serum response factor
(SRF; 600589), class I bHLH proteins, such as E12 (147141), HEB
(600480), and E2-2 (602272), and the bHLH inhibitors ID (see ID1;
600349) and TWIST (601622) are likely important regulators of smooth
muscle cell differentiation.
MOLECULAR GENETICS
The major function of vascular smooth muscle cells (SMCs) is contraction
to regulate blood pressure and flow. SMC contractile force requires
cyclic interactions between SMC alpha-actin, encoded by ACTA2, and the
beta-myosin heavy chain, encoded by the MYH11 gene (160745). Guo et al.
(2007) showed that missense mutations in ACTA2 are responsible for 14%
of inherited ascending thoracic aortic aneurysms and dissections (AAT6;
611788). Structural analyses and immunofluorescence of actin filaments
in SMCs derived from individuals heterozygous for ACTA2 mutations
illustrated that these mutations interfere with actin filament assembly
and are predicted to decrease SMC contraction. Aortic tissues from
affected individuals showed aortic medial degeneration, focal areas of
medial SMC hyperplasia and disarray, and stenotic arteries in the vasa
vasorum due to medial SMC proliferation. These data, along with the
previously reported MYH11 mutations causing familial thoracic aortic
aneurysm, indicate the importance of SMC contraction in maintaining the
structural integrity of the ascending aorta. Since mutations in 2
components of the SMC contractile unit, ACTA2 and MYH11, cause familial
thoracic aortic aneurysm with dissection (TAAD), Guo et al. (2007)
raised the possibility that mutations in other components of the SMC
contractile unit may be responsible for a portion of the 80% of familial
TAAD yet to be explained.
Guo et al. (2007) found that the penetrance of TAAD in individuals with
ACTA2 mutations was low (0.48) and did not increase with age, differing
from the pattern for other identified loci and genes for familial TAAD,
which have a higher, age-related penetrance. Despite the young age of
death of some family members, the Kaplan-Meier survival curve of the
ACTA2 cohort estimated a median survival of 67 years, suggesting that
the disease is less deadly than Loeys-Dietz syndrome (609192) and
similar to treated Marfan syndrome (MFS; 154700).
Guo et al. (2009) studied 20 families with 127 members harboring
heterozygous ACTA2 mutations and phenotyped them for premature vascular
disease, defined as an age of onset less than 55 years in men and less
than 60 years in women. Family members aged 21 years and older were
included, along with members who presented with vascular diseases at
younger ages. Thoracic aortic aneurysm had been reported in 14 of these
20 families by Guo et al. (2007). The 6 additional families with ACTA2
mutations all carried missense mutations. None of these missense
mutations was identified in 192 ethnically matched controls. Thoracic
aortic aneurysm was the primary vascular disease in ACTA2 mutation
carriers (76 individuals); 26 individuals had premature onset of
coronary artery disease, and 15 had ischemic strokes. Fifteen
individuals had more than 1 vascular disease, and none of the family
members without an ACTA2 mutation had any of these early-onset vascular
diseases. One family had more mutation carriers with premature coronary
artery disease than with aortic disease. In 3 families with an ACTA2
mutation altering the arginine-258 residue (arg258 to cys, 102620.0003,
arg258 to his, 102620.0002), 10 of 14 mutation carriers had aortic
disease and 7 had onset of strokes at ages ranging from 5 to 46 years.
Five of the 7 acute strokes had been classified as moyamoya disease
(MYMY5; 614042); 2 others had fusiform cerebral aneurysms.
Shimojima and Yamamoto (2009) analyzed all coding exons of the ACTA2
gene in 53 Japanese patients with moyamoya disease but found no
mutations. Noting that the diagnosis of moyamoya disease in the patients
studied by Guo et al. (2009) was unclear, Shimojima and Yamamoto (2009)
concluded that ACTA2 is not a major disease-causing gene for moyamoya
disease in Japanese patients.
Milewicz et al. (2010) identified 7 unrelated patients with a de novo
missense mutation in the ACTA2 gene (102620.0004) who presented with a
multisystemic smooth muscle dysfunction syndrome (613834), including
vasculopathy, congenital mydriasis, patent ductus arteriosus, and
thoracic aortic aneurysm.
Roder et al. (2011) identified a heterozygous mutation in the ACTA2 gene
(R179H; 102620.0004) in 1 of 39 unrelated patients of European descent
with moyamoya disease who had no family history of the disorder. No
other previously described ACTA2 mutations associated with moyamoya
disease (Guo et al., 2009) were found in this cohort.
In 40 German probands with thoracic aortic aneurysms, 21 of whom had
clinical features suggestive of Marfan syndrome, but all of whom were
negative for mutation in the FBN1 (134797) and TGFBR2 (190182) genes,
Hoffjan et al. (2011) sequenced the ACTA2 gene and identified
heterozygous mutations in 3 patients (see, e.g., 102620.0005 and
102620.0006). None of the 21 individuals with features suggestive of MFS
were found to carry a mutation in ACTA2. Among the remaining 19
patients, there were no differences between the 3 patients with ACTA2
mutations and the nonmutated patients. The authors also noted that there
was no history of premature stroke or coronary artery disease in the
mutation-positive families.
*FIELD* AV
.0001
AORTIC ANEURYSM, FAMILIAL THORACIC 6
ACTA2, ARG149CYS
In a large family in which thoracic aortic aneurysm with dissection
segregated with reduced penetrance (AAT6; 611788), Guo et al. (2007)
found a heterozygous 492C-T transition in exon 5 of the ACTA2 gene that
caused an arg149-to-cys (R149C) amino acid substitution. In further
studies, 4 additional families with the ACTA2 mutation were found;
however, each family had a unique haplotype, implying that the mutations
arose de novo in multiple families. Livedo reticularis and iris flocculi
were found together or separately in some of these families.
Guo et al. (2009) analyzed 45 individuals with the R149C mutation and
found that, in addition to the already established predisposition to
TAAD, this mutation led to coronary artery disease (24 mutation carriers
with TAAD, 12 with coronary artery disease).
.0002
AORTIC ANEURYSM, FAMILIAL THORACIC 6
MOYAMOYA DISEASE 5, INCLUDED
ACTA2, ARG258HIS
In a family of European descent with hereditary thoracic aortic aneurysm
with dissection (AAT6; 611788), Guo et al. (2007) identified an 820G-A
transition in exon 7 of the ACTA2 gene, resulting in an arg258-to-his
(R258H) substitution. One individual in the family had patent ductus
arteriosus.
Guo et al. (2009) analyzed 15 individuals carrying a missense mutation
at arg258 and found that, in addition to the already established
predisposition to TAAD, mutation at this position was associated with
stroke (10 individuals with TAAD, 7 with stroke). In 1 family with the
R258H mutation, 3 affected individuals had a phenotype consistent with
moyamoya disease-5 (MYMY5; 614042). Two of these 3 patients had strokes
at ages 44 and 46 years, respectively, and also had thoracic aortic
aneurysm with dissection; the third had isolated moyamoya disease with
stroke at age 16 years. The findings indicated that ACTA2 mutations can
cause a spectrum of vascular diseases, even within a single family.
.0003
AORTIC ANEURYSM, FAMILIAL THORACIC 6
MOYAMOYA DISEASE 5, INCLUDED
ACTA2, ARG258CYS
In 2 families of European descent with hereditary thoracic aortic
aneurysm with dissection (AAT6; 611788), Guo et al. (2007) identified an
819C-T transition in exon 7 of the ACTA2 gene, resulting in an
arg258-to-cys (R258C) substitution. All 5 mutation carriers in 1 family
had patent ductus arteriosus.
Guo et al. (2009) analyzed 15 individuals carrying a missense mutation
at arg258 and found that, in addition to the already established
predisposition to TAAD, mutation at this position was associated with
stroke (10 individuals with TAAD, 7 with stroke). The authors identified
a high risk of early-onset strokes in family members carrying the R258C
mutation. In 1 family with the R258C mutation, 2 members had a phenotype
consistent with moyamoya disease-5 (614042), with strokes at ages 39 and
5 years, respectively. The older patient had thoracic aneurysm with
dissection at age 32 years, whereas the stroke was fatal in the younger
patient. The findings indicated that ACTA2 mutations can cause a
spectrum of vascular diseases, even within a single family.
.0004
MULTISYSTEMIC SMOOTH MUSCLE DYSFUNCTION SYNDROME
MOYAMOYA DISEASE 5, INCLUDED
ACTA2, ARG179HIS
In 7 unrelated patients of northern European descent with multisystemic
smooth muscle dysfunction syndrome (613834), Milewicz et al. (2010)
identified heterozygosity for a de novo arg179-to-his (R179H)
substitution in the ACTA2 gene. The mutation was not identified in
parents' DNA samples, confirming the de novo status in 5 patients. Three
of the patients had been previously reported (Ades et al., 1999, Kahn et
al., 2004, and Lemire et al., 2004, respectively).
Roder et al. (2011) identified a heterozygous R179H mutation in 1 of 39
patients of European origin with moyamoya disease-5 (614042) and no
family history of the disorder. The patient was a girl who had a stroke
at age 3 years, but she had no other abnormalities, particularly none of
those described by Milewicz et al. (2010).
.0005
AORTIC ANEURYSM, FAMILIAL THORACIC 6
ACTA2, ARG39CYS
In a 3-generation German family with autosomal dominant thoracic aortic
aneurysm (AAT6; 611788), Hoffjan et al. (2011) identified heterozygosity
for a c.115C-T transition in exon 2 of the ACTA2 gene, resulting in an
arg39-to-cys (R39C) substitution at a highly conserved residue adjacent
to the DNAse-I-binding loop within subdomain 2. The mutation segregated
with disease in the family and was not found in 192 control chromosomes
or in the GenBank dbSNP library. The vascular phenotype was variable in
this family, ranging from mild aortic dilation and insufficiency in a
44-year-old woman to overt aortic aneurysm extending from the ascending
to the abdominal aorta in a 25-year-old man. None of the affected
individuals showed syndromic features, and there was no history of
premature stroke or coronary artery disease. Hoffjan et al. (2011) noted
that although a different mutation at the R39 residue, R39H, had been
associated with type A dissections in 2 families and with type B
dissections in another family (Guo et al., 2009), dissections were not
observed in the family with the R39C mutation.
.0006
AORTIC ANEURYSM, FAMILIAL THORACIC 6
ACTA2, MET49VAL
In a German woman who presented with acute aortic dissection at 37 years
of age, Hoffjan et al. (2011) identified heterozygosity for a c.145A-G
transition in exon 3 of the ACTA2 gene, resulting in a met49-to-val
(M49V) substitution at a highly conserved residue in the DNAse-I-binding
loop within subdomain 2. The mutation was not found in 192 control
chromosomes or in the GenBank dbSNP library. The patient's brother had
died at 29 years of age from acute aortic dissection, and her mother,
who suffered from slowly progressive spastic paraplegia over 20 years
and cancer, died suddenly at 69 years of age in association with a
massive drop in blood pressure.
*FIELD* RF
1. Ades, L. C.; Davies, R.; Haan, E. A.; Holman, K. J.; Watson, K.
C.; Sreetharan, D.; Cao, S. N.; Milewicz, D. M.; Bateman, J. F.; Chiodo,
A. A.; Eccles, M.; McNoe, L.; Harbord, M.: Aortic dissection, patent
ductus arteriosus, iris hypoplasia and brachytelephalangy in a male
adolescent. Clin. Dysmorph. 8: 269-276, 1999.
2. Guo, D.-C.; Pannu, H.; Tran-Fadulu, V.; Papke, C. L.; Yu, R. K.;
Avidan, N.; Bourgeois, S.; Estrera, A. L.; Safi, H. J.; Sparks, E.;
Amor, D.; Ades, L.; and 13 others: Mutations in smooth muscle alpha-actin
(ACTA2) lead to thoracic aortic aneurysms and dissections. Nature
Genet. 39: 1488-1493, 2007. Note: Erratum: Nature Genet. 40: 255
only, 2008.
3. Guo, D.-C.; Papke, C. L.; Tran-Fadulu, V.; Regalado, E. S.; Avidan,
N.; Johnson, R. J.; Kim, D. H.; Pannu, H.; Willing, M. C.; Sparks,
E.; Pyeritz, R. E.; Singh, M. N.; and 19 others: Mutations in smooth
muscle alpha-actin (ACTA2) cause coronary artery disease, stroke,
and Moyamoya disease, along with thoracic aortic disease. Am. J.
Hum. Genet. 84: 617-627, 2009.
4. Hoffjan, S.; Waldmuller, S.; Blankenfeldt, W.; Kotting, J.; Gehle,
P.; Binner, P.; Epplen, J. T.; Scheffold, T.: Three novel mutations
in the ACTA2 gene in German patients with thoracic aortic aneurysms
and dissections. Europ. J. Hum. Genet. 19: 520-524, 2011.
5. Kahn, N.; Schinzel, A.; Shuknecht, B.; Baumann, F.; Ostergaard,
J. R.; Yonekawa, Y.: Moyamoya angiopathy with dolichoectatic internal
carotid arteries, patent ductus arteriosus and pupillary dysfunction:
a new genetic syndrome? Europ. Neurol. 51: 72-77, 2004.
6. Kumar, M. S.; Hendrix, J. A.; Johnson, A. D.; Owens, G. K.: Smooth
muscle alpha-actin gene requires two E-boxes for proper expression
in vivo and is a target of class I basic helix-loop-helix proteins. Circ.
Res. 92: 840-847, 2003.
7. Lemire, B. D.; Buncic, J. R.; Kennedy, S. J.; Dyack, S. J.; Teebi,
A. S.: Congenital mydriasis, patent ductus arteriosus, and congenital
cystic lung disease: new syndromic spectrum? Am. J. Med. Genet. 131:
318-319, 2004.
8. Milewicz, D. M.; Ostergaard, J. R.; Ala-Kokko, L. M.; Khan, N.;
Grange, D. K.; Mendoza-Londono, R.; Bradley, T. J.; Olney, A. H.;
Ades, L.; Maher, J. F.; Guo, D.; Buja, L. M.; Kim, D.; Hyland, J.
C.; Regalado, E. S.: De novo ACTA2 mutation causes a novel syndrome
of multisystemic smooth muscle dysfunction. Am. J. Med. Genet. 152A:
2437-2443, 2010.
9. Roder, C.; Peters, V.; Kasuya, H.; Nishizawa, T.; Wakita, S.; Berg,
D.; Schulte, C.; Khan, N.; Tatagiba, M.; Krischek, B.: Analysis of
ACTA2 in European Moyamoya disease patients. Europ. J. Paediat. Neurol. 15:
117-122, 2011.
10. Shimojima, K.; Yamamoto, T.: ACTA2 is not a major disease-causing
gene for moyamoya disease. (Letter) J. Hum. Genet. 54: 687-688,
2009.
11. Ueyama, H.; Bruns, G.; Kanda, N.: Assignment of the vascular
smooth muscle actin gene ACTSA to human chromosome 10. Jinrui Idengaku
Zasshi 35: 145-150, 1990.
12. Ueyama, H.; Hamada, H.; Battula, N.; Kakunaga, T.: Structure
of a human smooth muscle actin gene (aortic type) with a unique intron
site. Molec. Cell. Biol. 4: 1073-1078, 1984.
13. 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.
14. Vandekerckhove, J.; Weber, K.: The complete amino acid sequence
of actins from bovine aorta, bovine heart, bovine fast skeletal muscle,
and rabbit slow skeletal muscle. Differentiation 14: 123-133, 1979.
*FIELD* CN
Marla J. F. O'Neill - updated: 09/24/2013
Cassandra L. Kniffin - updated: 6/14/2011
Ada Hamosh - updated: 3/24/2011
Ada Hamosh - updated: 10/6/2009
Victor A. McKusick - updated: 12/20/2007
Patricia A. Hartz - updated: 3/24/2004
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 09/24/2013
carol: 5/30/2012
wwang: 6/27/2011
ckniffin: 6/14/2011
terry: 4/25/2011
wwang: 3/25/2011
terry: 3/24/2011
wwang: 6/11/2010
alopez: 10/12/2009
terry: 10/6/2009
carol: 12/10/2008
alopez: 6/24/2008
terry: 12/20/2007
mgross: 4/14/2004
terry: 3/24/2004
terry: 6/16/1995
supermim: 3/16/1992
carol: 2/27/1992
carol: 7/3/1991
carol: 3/19/1991
carol: 9/27/1990
MIM
611788
*RECORD*
*FIELD* NO
611788
*FIELD* TI
#611788 AORTIC ANEURYSM, FAMILIAL THORACIC 6; AAT6
;;FAMILIAL THORACIC AORTIC ANEURYSM WITH LIVEDO RETICULARIS AND IRIS
read moreFLOCCULI
*FIELD* TX
A number sign (#) is used with this entry because thoracic aortic
aneurysm-6 (AAT6) is caused by heterozygous mutation in the ACTA2 gene
(102620), encoding vascular smooth muscle actin, on chromosome 10q23.
For a general phenotypic description and a discussion of genetic
heterogeneity of familial thoracic aortic aneurysm, see 607086.
See also moyamoya disease-5 (MYMY5; 614042), another vascular disorder
caused by mutation in the ACTA2 gene.
CLINICAL FEATURES
Guo et al. (2007) identified a large family with autosomal dominant
inheritance, with decreased penetrance, of thoracic aortic aneurysms
leading to acute aortic dissections (TAAD). Segregation of the disorder
was not linked to any known locus. On examination, the only physical
feature present in all family members was pronounced and persistent
livedo reticularis (see 182410), a purplish skin discoloration in a
network pattern due to constriction or occlusion of deep dermal
capillaries, clearly visible on arms and legs. In other families with a
similar phenotype, iris flocculi was also present. Patent ductus
arteriosus (PDA) was present in 6 affected individuals from 2 families,
and bicuspid aortic valve (BAV) in 4 individuals from 3 families.
The majority of individuals with AAT6 studied by Guo et al. (2007)
presented with acute ascending (type A) or descending (type B) aortic
dissections, and 16 of the 24 deaths were due to type A dissections. Two
individuals experienced type A dissections with documented ascending
aortic diameters at 4.5 and 4.6 cm, whereas 11 individuals dissected at
aortic diameters greater than 5.0 cm. Aortic dissections occurred in 3
individuals under 20 years of age, and 2 women died of dissections
postpartum. In 3 young men, type B dissection complicated by rupture or
aneurysm formation occurred at the ages of 13, 16, and 21 years. Despite
the young age of death of some family members, the Kaplan-Meier survival
curve of the cohort estimated a median survival of 67 years, suggesting
that the disease is less deadly than Loeys-Dietz syndrome (see 609192)
and similar to treated Marfan syndrome (MFS; 154700).
Bixler and Antley (1976) reported an association of familial aortic
dissection and ectopia of the pigment layer of the iris onto the
anterior surface of the iris. In 1 patient this created an appearance
suggesting coloboma. McKusick (1986) observed a similar eye finding in a
family seen with Dr. Robert L. Berger in the Moore Clinic. Lewis and
Merin (1995) noted the association of livedo reticularis and iris
flocculi with familial thoracic aortic aneurysms.
MAPPING
Guo et al. (2007) mapped the phenotype in a family with TAAD and livedo
reticularis to chromosome 10q23-q24 using genomewide linkage analysis
followed by typing of microsatellite markers. The authors designated
this locus TAAD4.
MOLECULAR GENETICS
In the family described by them with thoracic aortic aneurysms and
dissections and livedo reticularis linked to 10q23-q24, Guo et al.
(2007) identified an arg149-to-cys substitution in the ACTA2 gene
(R149C; 102620.0001). The mutation segregated with livedo reticularis in
the family with a lod score of 5.85. These results suggested that the
R149C ACTA2 mutation was responsible for both thoracic aortic aneurysm
and livedo reticularis in the initially studied family. Sequencing of
the ACTA2 gene in 97 unrelated families with a similar phenotype
identified 14 additional families with ACTA2 mutations. A total of 5
families carried the R149C mutation, which was shown by haplotype
analysis to have arisen de novo in each. The authors commented that
another form of thoracic aortic aneurysm with dissection (AAT4; 132900),
caused by mutations in another component of the smooth muscle cell
contractile unit, MYH11 (160745), is also associated with PDA in some
affected individuals. Structural analyses and immunofluorescence of
actin filaments in smooth muscle cells (SMCs) derived from individuals
heterozygous for ACTA2 mutations illustrated that these mutations
interfere with actin filament assembly and are predicted to decrease SMC
contraction. Aortic tissues from affected individuals showed aortic
medial degeneration, focal areas of medial SMC hyperplasia and disarray,
and stenotic arteries in the vasa vasorum due to medial SMC
proliferation. These data, along with the previously reported MYH11
mutations causing familial thoracic aortic aneurysm, indicate the
importance of SMC contraction in maintaining the structural integrity of
the ascending aorta.
Guo et al. (2009) studied 20 families with 127 members harboring
heterozygous ACTA2 mutations and phenotyped them for premature vascular
disease, defined as an age of onset less than 55 years in men and less
than 60 years in women. Thoracic aortic aneurysm had been reported in 14
of these 20 families by Guo et al. (2007). Thoracic aortic aneurysm was
the primary vascular disease in ACTA2 mutation carriers (76
individuals); 26 individuals had premature onset of coronary artery
disease, and 15 had ischemic strokes.
In 40 German probands with thoracic aortic aneurysms, 21 of whom had
clinical features suggestive of Marfan syndrome, but all of whom were
negative for mutation in the FBN1 (134797) and TGFBR2 (190182) genes,
Hoffjan et al. (2011) sequenced the ACTA2 gene and identified
heterozygous mutations in 3 patients (see, e.g., 102620.0005 and
102620.0006). None of the 21 individuals with features suggestive of MFS
were found to carry a mutation in ACTA2. Among the remaining 19
patients, there were no differences between the 3 patients with ACTA2
mutations and the nonmutated patients. The authors also noted that there
was no history of premature stroke or coronary artery disease in the
mutation-positive families.
*FIELD* RF
1. Bixler, D.; Antley, R. M.: Familial aortic dissection with iris
anomalies--a new connective tissue disease syndrome? Birth Defects
Orig. Art. Ser. XII(5): 229-234, 1976.
2. Guo, D.-C.; Pannu, H.; Tran-Fadulu, V.; Papke, C. L.; Yu, R. K.;
Avidan, N.; Bourgeois, S.; Estrera, A. L.; Safi, H. J.; Sparks, E.;
Amor, D.; Ades, L.; and 13 others: Mutations in smooth muscle alpha-actin
(ACTA2) lead to thoracic aortic aneurysms and dissections. Nature
Genet. 39: 1488-1493, 2007. Note: Erratum: Nature Genet. 40: 255
only, 2008.
3. Guo, D.-C.; Papke, C. L.; Tran-Fadulu, V.; Regalado, E. S.; Avidan,
N.; Johnson, R. J.; Kim, D. H.; Pannu, H.; Willing, M. C.; Sparks,
E.; Pyeritz, R. E.; Singh, M. N.; and 19 others: Mutations in smooth
muscle alpha-actin (ACTA2) cause coronary artery disease, stroke,
and Moyamoya disease, along with thoracic aortic disease. Am. J.
Hum. Genet. 84: 617-627, 2009.
4. Hoffjan, S.; Waldmuller, S.; Blankenfeldt, W.; Kotting, J.; Gehle,
P.; Binner, P.; Epplen, J. T.; Scheffold, T.: Three novel mutations
in the ACTA2 gene in German patients with thoracic aortic aneurysms
and dissections. Europ. J. Hum. Genet. 19: 520-524, 2011.
5. Lewis, R. A.; Merin, L. M.: Iris flocculi and familial aortic
dissection. Arch. Ophthal. 113: 1330-1331, 1995.
6. McKusick, V. A.: Personal Communication. Baltimore, Md. 6/4/1986.
*FIELD* CN
Marla J. F. O'Neill - updated: 09/24/2013
Ada Hamosh - updated: 10/6/2009
*FIELD* CD
Victor A. McKusick: 2/12/2008
*FIELD* ED
carol: 09/24/2013
carol: 5/30/2012
wwang: 6/27/2011
ckniffin: 6/14/2011
alopez: 10/12/2009
terry: 10/6/2009
carol: 7/3/2008
alopez: 6/24/2008
*RECORD*
*FIELD* NO
611788
*FIELD* TI
#611788 AORTIC ANEURYSM, FAMILIAL THORACIC 6; AAT6
;;FAMILIAL THORACIC AORTIC ANEURYSM WITH LIVEDO RETICULARIS AND IRIS
read moreFLOCCULI
*FIELD* TX
A number sign (#) is used with this entry because thoracic aortic
aneurysm-6 (AAT6) is caused by heterozygous mutation in the ACTA2 gene
(102620), encoding vascular smooth muscle actin, on chromosome 10q23.
For a general phenotypic description and a discussion of genetic
heterogeneity of familial thoracic aortic aneurysm, see 607086.
See also moyamoya disease-5 (MYMY5; 614042), another vascular disorder
caused by mutation in the ACTA2 gene.
CLINICAL FEATURES
Guo et al. (2007) identified a large family with autosomal dominant
inheritance, with decreased penetrance, of thoracic aortic aneurysms
leading to acute aortic dissections (TAAD). Segregation of the disorder
was not linked to any known locus. On examination, the only physical
feature present in all family members was pronounced and persistent
livedo reticularis (see 182410), a purplish skin discoloration in a
network pattern due to constriction or occlusion of deep dermal
capillaries, clearly visible on arms and legs. In other families with a
similar phenotype, iris flocculi was also present. Patent ductus
arteriosus (PDA) was present in 6 affected individuals from 2 families,
and bicuspid aortic valve (BAV) in 4 individuals from 3 families.
The majority of individuals with AAT6 studied by Guo et al. (2007)
presented with acute ascending (type A) or descending (type B) aortic
dissections, and 16 of the 24 deaths were due to type A dissections. Two
individuals experienced type A dissections with documented ascending
aortic diameters at 4.5 and 4.6 cm, whereas 11 individuals dissected at
aortic diameters greater than 5.0 cm. Aortic dissections occurred in 3
individuals under 20 years of age, and 2 women died of dissections
postpartum. In 3 young men, type B dissection complicated by rupture or
aneurysm formation occurred at the ages of 13, 16, and 21 years. Despite
the young age of death of some family members, the Kaplan-Meier survival
curve of the cohort estimated a median survival of 67 years, suggesting
that the disease is less deadly than Loeys-Dietz syndrome (see 609192)
and similar to treated Marfan syndrome (MFS; 154700).
Bixler and Antley (1976) reported an association of familial aortic
dissection and ectopia of the pigment layer of the iris onto the
anterior surface of the iris. In 1 patient this created an appearance
suggesting coloboma. McKusick (1986) observed a similar eye finding in a
family seen with Dr. Robert L. Berger in the Moore Clinic. Lewis and
Merin (1995) noted the association of livedo reticularis and iris
flocculi with familial thoracic aortic aneurysms.
MAPPING
Guo et al. (2007) mapped the phenotype in a family with TAAD and livedo
reticularis to chromosome 10q23-q24 using genomewide linkage analysis
followed by typing of microsatellite markers. The authors designated
this locus TAAD4.
MOLECULAR GENETICS
In the family described by them with thoracic aortic aneurysms and
dissections and livedo reticularis linked to 10q23-q24, Guo et al.
(2007) identified an arg149-to-cys substitution in the ACTA2 gene
(R149C; 102620.0001). The mutation segregated with livedo reticularis in
the family with a lod score of 5.85. These results suggested that the
R149C ACTA2 mutation was responsible for both thoracic aortic aneurysm
and livedo reticularis in the initially studied family. Sequencing of
the ACTA2 gene in 97 unrelated families with a similar phenotype
identified 14 additional families with ACTA2 mutations. A total of 5
families carried the R149C mutation, which was shown by haplotype
analysis to have arisen de novo in each. The authors commented that
another form of thoracic aortic aneurysm with dissection (AAT4; 132900),
caused by mutations in another component of the smooth muscle cell
contractile unit, MYH11 (160745), is also associated with PDA in some
affected individuals. Structural analyses and immunofluorescence of
actin filaments in smooth muscle cells (SMCs) derived from individuals
heterozygous for ACTA2 mutations illustrated that these mutations
interfere with actin filament assembly and are predicted to decrease SMC
contraction. Aortic tissues from affected individuals showed aortic
medial degeneration, focal areas of medial SMC hyperplasia and disarray,
and stenotic arteries in the vasa vasorum due to medial SMC
proliferation. These data, along with the previously reported MYH11
mutations causing familial thoracic aortic aneurysm, indicate the
importance of SMC contraction in maintaining the structural integrity of
the ascending aorta.
Guo et al. (2009) studied 20 families with 127 members harboring
heterozygous ACTA2 mutations and phenotyped them for premature vascular
disease, defined as an age of onset less than 55 years in men and less
than 60 years in women. Thoracic aortic aneurysm had been reported in 14
of these 20 families by Guo et al. (2007). Thoracic aortic aneurysm was
the primary vascular disease in ACTA2 mutation carriers (76
individuals); 26 individuals had premature onset of coronary artery
disease, and 15 had ischemic strokes.
In 40 German probands with thoracic aortic aneurysms, 21 of whom had
clinical features suggestive of Marfan syndrome, but all of whom were
negative for mutation in the FBN1 (134797) and TGFBR2 (190182) genes,
Hoffjan et al. (2011) sequenced the ACTA2 gene and identified
heterozygous mutations in 3 patients (see, e.g., 102620.0005 and
102620.0006). None of the 21 individuals with features suggestive of MFS
were found to carry a mutation in ACTA2. Among the remaining 19
patients, there were no differences between the 3 patients with ACTA2
mutations and the nonmutated patients. The authors also noted that there
was no history of premature stroke or coronary artery disease in the
mutation-positive families.
*FIELD* RF
1. Bixler, D.; Antley, R. M.: Familial aortic dissection with iris
anomalies--a new connective tissue disease syndrome? Birth Defects
Orig. Art. Ser. XII(5): 229-234, 1976.
2. Guo, D.-C.; Pannu, H.; Tran-Fadulu, V.; Papke, C. L.; Yu, R. K.;
Avidan, N.; Bourgeois, S.; Estrera, A. L.; Safi, H. J.; Sparks, E.;
Amor, D.; Ades, L.; and 13 others: Mutations in smooth muscle alpha-actin
(ACTA2) lead to thoracic aortic aneurysms and dissections. Nature
Genet. 39: 1488-1493, 2007. Note: Erratum: Nature Genet. 40: 255
only, 2008.
3. Guo, D.-C.; Papke, C. L.; Tran-Fadulu, V.; Regalado, E. S.; Avidan,
N.; Johnson, R. J.; Kim, D. H.; Pannu, H.; Willing, M. C.; Sparks,
E.; Pyeritz, R. E.; Singh, M. N.; and 19 others: Mutations in smooth
muscle alpha-actin (ACTA2) cause coronary artery disease, stroke,
and Moyamoya disease, along with thoracic aortic disease. Am. J.
Hum. Genet. 84: 617-627, 2009.
4. Hoffjan, S.; Waldmuller, S.; Blankenfeldt, W.; Kotting, J.; Gehle,
P.; Binner, P.; Epplen, J. T.; Scheffold, T.: Three novel mutations
in the ACTA2 gene in German patients with thoracic aortic aneurysms
and dissections. Europ. J. Hum. Genet. 19: 520-524, 2011.
5. Lewis, R. A.; Merin, L. M.: Iris flocculi and familial aortic
dissection. Arch. Ophthal. 113: 1330-1331, 1995.
6. McKusick, V. A.: Personal Communication. Baltimore, Md. 6/4/1986.
*FIELD* CN
Marla J. F. O'Neill - updated: 09/24/2013
Ada Hamosh - updated: 10/6/2009
*FIELD* CD
Victor A. McKusick: 2/12/2008
*FIELD* ED
carol: 09/24/2013
carol: 5/30/2012
wwang: 6/27/2011
ckniffin: 6/14/2011
alopez: 10/12/2009
terry: 10/6/2009
carol: 7/3/2008
alopez: 6/24/2008
MIM
613834
*RECORD*
*FIELD* NO
613834
*FIELD* TI
#613834 MULTISYSTEMIC SMOOTH MUSCLE DYSFUNCTION SYNDROME
;;MYDRIASIS, CONGENITAL, WITH PATENT DUCTUS ARTERIOSUS, THORACIC AORTIC
read moreANEURYSM, AND VASCULOPATHY
*FIELD* TX
A number sign (#) is used with this entry because multisystemic smooth
muscle dysfunction syndrome can be caused by mutation in the ACTA2 gene
(102620).
See also familial thoracic aortic aneurysm (AAT6; 611788), which can
also be caused by ACTA2 mutation.
CLINICAL FEATURES
Milewicz et al. (2010) described 7 unrelated patients ranging in age
from 11 to 27 years who had clinical findings suggestive of vascular
disease, consistent with previous ACTA2 mutations. However, there was
higher penetrance and earlier onset of vascular disease and additional
multisystem smooth muscle dysfunction was manifest. Three of these
patients had been previously described by Kahn et al. (2004), Lemire et
al. (2004), and Ades et al. (1999), respectively. All patients shared
the features of congenital mydriasis or fixed dilated pupils, as well as
patent ductus arteriosus requiring repair in infancy. The patient
previously reported by Lemire et al. (2004) had aortic coarctation that
was repaired at age 4 months. All patients subsequently developed
fusiform ascending aortic aneurysms extending to the arch during
childhood, and 5 of 7 required surgical repair at age 10 to 25 years.
The patient previously reported by Ades et al. (1999) had a dissection
at 14 years of age. In addition to the aortic disease, all patients had
cerebral vascular abnormalities including fusiform dilatation of the
intimal carotid artery from the cavernous to the clinoidal segments, and
the terminal region of the internal carotid arteries showed mild to
moderate tapering indicative of stenosis of the artery and consistent
with changes observed in Moyamoya disease (see 252350). Two of the
patients, one reported by Milewicz et al. (2010) and one reported by
Kahn et al. (2004), underwent neurosurgical bypass for revascularization
for Moyamoya disease. All 5 patients for whom imaging was reported had
bilateral periventricular white matter hyperintensities, and 1 had
changes consistent with a middle and anterior cerebral artery stroke.
One patient had colpocephaly with a thin corpus callosum and somewhat
small cerebral vermis and was diagnosed with developmental delay. In
addition to the vascular abnormality, additional evidence of smooth
muscle dysfunction included congenital mydriasis, hypotonic bladder,
malrotation, and hyperperistalsis of the GI tract. Two patients had
malrotation. One patient had gallstones that spontaneously resolved and
subsequently presented with hydrops of the gallbladder without evidence
of residual gallstones. Biopsies of the esophagus, stomach, and small
intestine revealed normal ganglionic cells and no specific neural or
smooth muscle pathology. Four of the 5 patients for whom data were
available had tachypnea at birth. One patient had hyperinflation of the
upper lung segment, a hypoplastic lower lung segment, and a dilated
pulmonary trunk at 14 years of age. The patient previously reported by
Lemire et al. (2004) had evidence of cystic lung disease as an infant
with biopsies showing alveolar dysgenesis consistent with developmental
defect. One patient was diagnosed with primary pulmonary hypertension
and underwent bilateral lung transplantation at age 18 months. The lung
pathology showed pulmonary arterial hypertensive changes with smooth
muscle cell hyperplasia and neointimal fibrocellular proliferative
lesions. In addition, 2 out of 3 males had unilateral undescended
testes. Two of the patients had asthma, and several patients had
microaneurysms. One patient had microaneurysms of the retina, and one
had a right ophthalmic artery occlusion.
MOLECULAR GENETICS
In 7 unrelated patients of northern European descent with multisystemic
smooth muscle dysfunction syndrome, Milewicz et al. (2010) identified
heterozygosity for a de novo R179H mutation in the ACTA2 gene
(102620.0004).
*FIELD* RF
1. Ades, L. C.; Davies, R.; Haan, E. A.; Holman, K. J.; Watson, K.
C.; Sreetharan, D.; Cao, S.-N.; Milewicz, D. M.; Bateman, J. F.; Chiodo,
A. A.; Eccles, M.; McNoe, L.; Harbord, M.: Aortic dissection, patent
ductus arteriosus, iris hypoplasia and brachytelephalangy in a male
adolescent. Clin. Dysmorph. 8: 269-276, 1999.
2. Kahn, N.; Schinzel, A.; Shuknecht, B.; Baumann, F.; Ostergaard,
J. R.; Yonekawa, Y.: Moyamoya angiopathy with dolichoectatic internal
carotid arteries, patent ductus arteriosus and pupillary dysfunction:
a new genetic syndrome? Europ. Neurol. 51: 72-77, 2004.
3. Lemire, B. D.; Buncic, J. R.; Kennedy, S. J.; Dyack, S. J.; Teebi,
A. S.: Congenital mydriasis, patent ductus arteriosus, and congenital
cystic lung disease: new syndromic spectrum? Am. J. Med. Genet. 131A:
318-319, 2004.
4. Milewicz, D. M.; Ostergaard, J. R.; Ala-Kokko, L. M.; Khan, N.;
Grange, D. K.; Mendoza-Londono, R.; Bradley, T. J.; Olney, A. H.;
Ades, L.; Maher, J. F.; Guo, D.; Buja, L. M.; Kim, D.; Hyland, J.
C.; Regalado, E. S.: De novo ACTA2 mutation causes a novel syndrome
of multisystemic smooth muscle dysfunction. Am. J. Med. Genet. 152A:
2437-2443, 2010.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Mydriasis, congenital;
Small vessel retinal infarcts and aneurysms
CARDIOVASCULAR:
[Heart];
Patent ductus arteriosis;
[Vascular];
Thoracic aortic aneurysm;
Dilated pulmonary arteries;
Bilateral stenoses of the terminal internal carotid artery;
Small vessel brain infarcts and aneurysms;
Small vessel retinal infarcts and aneurysms;
Pulmonary hypertension
RESPIRATORY:
Tachypnea;
[Lung];
Lung disease, non-specific
ABDOMEN:
[Gastrointestinal];
Malrotation;
Hyperperistalsis
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism;
[Bladder];
Hypotonic bladder
NEUROLOGIC:
[Central nervous system];
Periventricular white matter hyperintensities, bilateral
MISCELLANEOUS:
All de novo mutations;
Seven patients reported (as of March 2011)
MOLECULAR BASIS:
Caused by mutation in the actin, alpha-2, smooth muscle, aorta gene
(ACTA2, 102620.0004)
*FIELD* CD
Ada Hamosh: 3/25/2011
*FIELD* ED
joanna: 12/30/2011
joanna: 3/25/2011
*FIELD* CD
Ada Hamosh: 3/25/2011
*FIELD* ED
terry: 04/13/2011
terry: 4/13/2011
wwang: 3/25/2011
*RECORD*
*FIELD* NO
613834
*FIELD* TI
#613834 MULTISYSTEMIC SMOOTH MUSCLE DYSFUNCTION SYNDROME
;;MYDRIASIS, CONGENITAL, WITH PATENT DUCTUS ARTERIOSUS, THORACIC AORTIC
read moreANEURYSM, AND VASCULOPATHY
*FIELD* TX
A number sign (#) is used with this entry because multisystemic smooth
muscle dysfunction syndrome can be caused by mutation in the ACTA2 gene
(102620).
See also familial thoracic aortic aneurysm (AAT6; 611788), which can
also be caused by ACTA2 mutation.
CLINICAL FEATURES
Milewicz et al. (2010) described 7 unrelated patients ranging in age
from 11 to 27 years who had clinical findings suggestive of vascular
disease, consistent with previous ACTA2 mutations. However, there was
higher penetrance and earlier onset of vascular disease and additional
multisystem smooth muscle dysfunction was manifest. Three of these
patients had been previously described by Kahn et al. (2004), Lemire et
al. (2004), and Ades et al. (1999), respectively. All patients shared
the features of congenital mydriasis or fixed dilated pupils, as well as
patent ductus arteriosus requiring repair in infancy. The patient
previously reported by Lemire et al. (2004) had aortic coarctation that
was repaired at age 4 months. All patients subsequently developed
fusiform ascending aortic aneurysms extending to the arch during
childhood, and 5 of 7 required surgical repair at age 10 to 25 years.
The patient previously reported by Ades et al. (1999) had a dissection
at 14 years of age. In addition to the aortic disease, all patients had
cerebral vascular abnormalities including fusiform dilatation of the
intimal carotid artery from the cavernous to the clinoidal segments, and
the terminal region of the internal carotid arteries showed mild to
moderate tapering indicative of stenosis of the artery and consistent
with changes observed in Moyamoya disease (see 252350). Two of the
patients, one reported by Milewicz et al. (2010) and one reported by
Kahn et al. (2004), underwent neurosurgical bypass for revascularization
for Moyamoya disease. All 5 patients for whom imaging was reported had
bilateral periventricular white matter hyperintensities, and 1 had
changes consistent with a middle and anterior cerebral artery stroke.
One patient had colpocephaly with a thin corpus callosum and somewhat
small cerebral vermis and was diagnosed with developmental delay. In
addition to the vascular abnormality, additional evidence of smooth
muscle dysfunction included congenital mydriasis, hypotonic bladder,
malrotation, and hyperperistalsis of the GI tract. Two patients had
malrotation. One patient had gallstones that spontaneously resolved and
subsequently presented with hydrops of the gallbladder without evidence
of residual gallstones. Biopsies of the esophagus, stomach, and small
intestine revealed normal ganglionic cells and no specific neural or
smooth muscle pathology. Four of the 5 patients for whom data were
available had tachypnea at birth. One patient had hyperinflation of the
upper lung segment, a hypoplastic lower lung segment, and a dilated
pulmonary trunk at 14 years of age. The patient previously reported by
Lemire et al. (2004) had evidence of cystic lung disease as an infant
with biopsies showing alveolar dysgenesis consistent with developmental
defect. One patient was diagnosed with primary pulmonary hypertension
and underwent bilateral lung transplantation at age 18 months. The lung
pathology showed pulmonary arterial hypertensive changes with smooth
muscle cell hyperplasia and neointimal fibrocellular proliferative
lesions. In addition, 2 out of 3 males had unilateral undescended
testes. Two of the patients had asthma, and several patients had
microaneurysms. One patient had microaneurysms of the retina, and one
had a right ophthalmic artery occlusion.
MOLECULAR GENETICS
In 7 unrelated patients of northern European descent with multisystemic
smooth muscle dysfunction syndrome, Milewicz et al. (2010) identified
heterozygosity for a de novo R179H mutation in the ACTA2 gene
(102620.0004).
*FIELD* RF
1. Ades, L. C.; Davies, R.; Haan, E. A.; Holman, K. J.; Watson, K.
C.; Sreetharan, D.; Cao, S.-N.; Milewicz, D. M.; Bateman, J. F.; Chiodo,
A. A.; Eccles, M.; McNoe, L.; Harbord, M.: Aortic dissection, patent
ductus arteriosus, iris hypoplasia and brachytelephalangy in a male
adolescent. Clin. Dysmorph. 8: 269-276, 1999.
2. Kahn, N.; Schinzel, A.; Shuknecht, B.; Baumann, F.; Ostergaard,
J. R.; Yonekawa, Y.: Moyamoya angiopathy with dolichoectatic internal
carotid arteries, patent ductus arteriosus and pupillary dysfunction:
a new genetic syndrome? Europ. Neurol. 51: 72-77, 2004.
3. Lemire, B. D.; Buncic, J. R.; Kennedy, S. J.; Dyack, S. J.; Teebi,
A. S.: Congenital mydriasis, patent ductus arteriosus, and congenital
cystic lung disease: new syndromic spectrum? Am. J. Med. Genet. 131A:
318-319, 2004.
4. Milewicz, D. M.; Ostergaard, J. R.; Ala-Kokko, L. M.; Khan, N.;
Grange, D. K.; Mendoza-Londono, R.; Bradley, T. J.; Olney, A. H.;
Ades, L.; Maher, J. F.; Guo, D.; Buja, L. M.; Kim, D.; Hyland, J.
C.; Regalado, E. S.: De novo ACTA2 mutation causes a novel syndrome
of multisystemic smooth muscle dysfunction. Am. J. Med. Genet. 152A:
2437-2443, 2010.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Mydriasis, congenital;
Small vessel retinal infarcts and aneurysms
CARDIOVASCULAR:
[Heart];
Patent ductus arteriosis;
[Vascular];
Thoracic aortic aneurysm;
Dilated pulmonary arteries;
Bilateral stenoses of the terminal internal carotid artery;
Small vessel brain infarcts and aneurysms;
Small vessel retinal infarcts and aneurysms;
Pulmonary hypertension
RESPIRATORY:
Tachypnea;
[Lung];
Lung disease, non-specific
ABDOMEN:
[Gastrointestinal];
Malrotation;
Hyperperistalsis
GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism;
[Bladder];
Hypotonic bladder
NEUROLOGIC:
[Central nervous system];
Periventricular white matter hyperintensities, bilateral
MISCELLANEOUS:
All de novo mutations;
Seven patients reported (as of March 2011)
MOLECULAR BASIS:
Caused by mutation in the actin, alpha-2, smooth muscle, aorta gene
(ACTA2, 102620.0004)
*FIELD* CD
Ada Hamosh: 3/25/2011
*FIELD* ED
joanna: 12/30/2011
joanna: 3/25/2011
*FIELD* CD
Ada Hamosh: 3/25/2011
*FIELD* ED
terry: 04/13/2011
terry: 4/13/2011
wwang: 3/25/2011
MIM
614042
*RECORD*
*FIELD* NO
614042
*FIELD* TI
#614042 MOYAMOYA DISEASE 5; MYMY5
*FIELD* TX
A number sign (#) is used with this entry because moyamoya disease-5
read more(MYMY5) is caused by heterozygous mutation in the ACTA2 gene (102620) on
chromosome 10q23.3.
See also familial thoracic aortic aneurysm-6 (AAT6; 611788), which is an
allelic vascular disorder.
DESCRIPTION
Moyamoya disease is a cerebrovascular disorder caused by stenotic
changes of terminal portions of the internal carotid arteries
accompanied by surrounding fine arterial collateral vessels. These
vascular networks resemble a 'puff of smoke' (Japanese: moyamoya) in
angiographic imaging (summary by Roder et al., 2011).
For a general phenotypic description and a discussion of genetic
heterogeneity of moyamoya disease, see MYMY1 (252350).
CLINICAL FEATURES
Guo et al. (2009) reported 3 unrelated families segregating both
thoracic aneurysms with dissection (TAAD) and moyamoya disease. Onset of
stroke in these families ranged from 5 to 46 years. Some patients had
isolated moyamoya, some had isolated thoracic aneurysm, and some had
both conditions.
INHERITANCE
The transmission pattern in the families reported by Guo et al. (2009)
was consistent with autosomal dominant inheritance.
MOLECULAR GENETICS
In affected members of 3 unrelated families with moyamoya disease, Guo
et al. (2009) identified 3 different heterozygous mutations in the ACTA2
gene (see, e.g., R258H, 102620.0002 and R258C, 102620.0003). Several
members of all families also had TAAD, but isolated moyamoya disease was
found in 1 member of each family.
Roder et al. (2011) identified a heterozygous mutation in the ACTA2 gene
(R179H; 102620.0004) in 1 of 39 unrelated patients of European descent
with moyamoya disease and no family history of the disorder. The patient
had onset of stroke at age 3 years. No other previously described ACTA2
mutations associated with moyamoya disease (Guo et al., 2009) were found
in this cohort.
*FIELD* RF
1. Guo, D.-C.; Papke, C. L.; Tran-Fadulu, V.; Regalado, E. S.; Avidan,
N.; Johnson, R. J.; Kim, D. H.; Pannu, H.; Willing, M. C.; Sparks,
E.; Pyeritz, R. E.; Singh, M. N.; and 19 others: Mutations in smooth
muscle alpha-actin (ACTA2) cause coronary artery disease, stroke,
and moyamoya disease, along with thoracic aortic disease. Am. J.
Hum. Genet. 84: 617-627, 2009.
2. Roder, C.; Peters, V.; Kasuya, H.; Nishizawa, T.; Wakita, S.; Berg,
D.; Schulte, C.; Khan, N.; Tatagiba, M.; Krischek, B.: Analysis of
ACTA2 in European moyamoya disease patients. Europ. J. Paediat. Neurol. 15:
117-122, 2011.
*FIELD* CD
Cassandra L. Kniffin: 6/14/2011
*FIELD* ED
terry: 09/29/2011
carol: 7/6/2011
wwang: 6/27/2011
ckniffin: 6/14/2011
*RECORD*
*FIELD* NO
614042
*FIELD* TI
#614042 MOYAMOYA DISEASE 5; MYMY5
*FIELD* TX
A number sign (#) is used with this entry because moyamoya disease-5
read more(MYMY5) is caused by heterozygous mutation in the ACTA2 gene (102620) on
chromosome 10q23.3.
See also familial thoracic aortic aneurysm-6 (AAT6; 611788), which is an
allelic vascular disorder.
DESCRIPTION
Moyamoya disease is a cerebrovascular disorder caused by stenotic
changes of terminal portions of the internal carotid arteries
accompanied by surrounding fine arterial collateral vessels. These
vascular networks resemble a 'puff of smoke' (Japanese: moyamoya) in
angiographic imaging (summary by Roder et al., 2011).
For a general phenotypic description and a discussion of genetic
heterogeneity of moyamoya disease, see MYMY1 (252350).
CLINICAL FEATURES
Guo et al. (2009) reported 3 unrelated families segregating both
thoracic aneurysms with dissection (TAAD) and moyamoya disease. Onset of
stroke in these families ranged from 5 to 46 years. Some patients had
isolated moyamoya, some had isolated thoracic aneurysm, and some had
both conditions.
INHERITANCE
The transmission pattern in the families reported by Guo et al. (2009)
was consistent with autosomal dominant inheritance.
MOLECULAR GENETICS
In affected members of 3 unrelated families with moyamoya disease, Guo
et al. (2009) identified 3 different heterozygous mutations in the ACTA2
gene (see, e.g., R258H, 102620.0002 and R258C, 102620.0003). Several
members of all families also had TAAD, but isolated moyamoya disease was
found in 1 member of each family.
Roder et al. (2011) identified a heterozygous mutation in the ACTA2 gene
(R179H; 102620.0004) in 1 of 39 unrelated patients of European descent
with moyamoya disease and no family history of the disorder. The patient
had onset of stroke at age 3 years. No other previously described ACTA2
mutations associated with moyamoya disease (Guo et al., 2009) were found
in this cohort.
*FIELD* RF
1. Guo, D.-C.; Papke, C. L.; Tran-Fadulu, V.; Regalado, E. S.; Avidan,
N.; Johnson, R. J.; Kim, D. H.; Pannu, H.; Willing, M. C.; Sparks,
E.; Pyeritz, R. E.; Singh, M. N.; and 19 others: Mutations in smooth
muscle alpha-actin (ACTA2) cause coronary artery disease, stroke,
and moyamoya disease, along with thoracic aortic disease. Am. J.
Hum. Genet. 84: 617-627, 2009.
2. Roder, C.; Peters, V.; Kasuya, H.; Nishizawa, T.; Wakita, S.; Berg,
D.; Schulte, C.; Khan, N.; Tatagiba, M.; Krischek, B.: Analysis of
ACTA2 in European moyamoya disease patients. Europ. J. Paediat. Neurol. 15:
117-122, 2011.
*FIELD* CD
Cassandra L. Kniffin: 6/14/2011
*FIELD* ED
terry: 09/29/2011
carol: 7/6/2011
wwang: 6/27/2011
ckniffin: 6/14/2011