KEGG   DISEASE: Hypertrophic cardiomyopathy
Entry
H00292                      Disease                                
Name
Hypertrophic cardiomyopathy
Description
Hypertrophic cardiomyopathy (HCM/CMH) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological features of myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. HCM is one of the most common inherited cardiac disorders, with a prevalence in young adults of 1 in 500. Hundreds of mutations in the genes that encode protein constituents of the sarcomere have been identified in HCM. These mutations increase the Ca2+ sensitivity of cardiac myofilaments. Increased myofilament Ca2+ sensitivity is expected to increase the ATP utilization by actomyosin at submaximal Ca2+ concentrations, which might cause an imbalance in energy supply and demand in the heart under severe stress. The inefficient use of ATP suggests that an inability to maintain normal ATP levels could be the central abnormality. This theory might be supported by the discovery of the role of a mutant PRKAG2 gene in HCM, which in active form acts as a central sensing mechanism protecting cells from depletion of ATP supplies. The increase in the myofilament Ca2+ sensitivity well account for the diastolic dysfunction of model animals as well as human patients of HCM. It has been widely proposed that left ventricular hypertrophy is not a primary manifestation but develops as compensatory response to sarcomere dysfunction.
Category
Cardiovascular disease
Brite
Human diseases [BR:br08402]
 Cardiovascular diseases
  Cardiac diseases
   H00292  Hypertrophic cardiomyopathy
Human diseases in ICD-11 classification [BR:br08403]
 11 Diseases of the circulatory system
  Diseases of the myocardium or cardiac chambers
   BC43  Cardiomyopathy
    H00292  Hypertrophic cardiomyopathy
Pathway
hsa05410  Hypertrophic cardiomyopathy
Related
pathway
hsa04260  Cardiac muscle contraction
hsa04261  Adrenergic signaling in cardiomyocytes
Gene
(CMH1) MYH7 [HSA:4625] [KO:K17751]
(CMH1) MYLK2 [HSA:85366] [KO:K00907]
(CMH1) CAV3 [HSA:859] [KO:K12959]
(CMH2) TNNT2 [HSA:7139] [KO:K12045]
(CMH3) TPM1 [HSA:7168] [KO:K10373]
(CMH4) MYBPC3 [HSA:4607] [KO:K12568]
(CMH6) PRKAG2 [HSA:51422] [KO:K07200]
(CMH7) TNNI3 [HSA:7137] [KO:K12044]
(CMH8) MYL3 [HSA:4634] [KO:K12749]
(CMH9) TTN [HSA:7273] [KO:K12567]
(CMH10) MYL2 [HSA:4633] [KO:K10351]
(CMH11) ACTC1 [HSA:70] [KO:K12314]
(CMH12) CSRP3 [HSA:8048] [KO:K09377]
(CMH13) TNNC1 [HSA:7134] [KO:K05865]
(CMH14) MYH6 [HSA:4624] [KO:K17751]
(CMH15) VCL [HSA:7414] [KO:K05700]
(CMH16) MYOZ2 [HSA:51778] [KO:K26050]
(CMH17) JPH2 [HSA:57158] [KO:K19530]
(CMH18) PLN [HSA:5350] [KO:K05852]
(CMH20) NEXN [HSA:91624] [KO:K23918]
(CMD1KK/CMH22) MYPN [HSA:84665] [KO:K22028]
(CMD1AA/CMH23) ACTN2 [HSA:88] [KO:K21073]
(CMD1C/CMH24) LDB3 [HSA:11155] [KO:K19867]
(CMH25) TCAP [HSA:8557] [KO:K19879]
(CMH26) FLNC [HSA:2318] [KO:K04437]
(CMH27) ALPK3 [HSA:57538] [KO:K08868]
(CMH28) FHOD3 [HSA:80206] [KO:K23939]
Env factor
Athletic training
Drug
Mavacamten [DR:D12265]
Other DBs
ICD-11: BC43.1
ICD-10: I42
OMIM: 192600 115195 115196 115197 600858 613690 608751 613765 608758 612098 612124 613243 613251 613255 613838 613873 613874 613876 615248 612158 601493 607487 617047 618052 619402
Reference
  Authors
Fatkin D, Graham RM
  Title
Molecular mechanisms of inherited cardiomyopathies.
  Journal
Physiol Rev 82:945-80 (2002)
DOI:10.1152/physrev.00012.2002
Reference
  Authors
Moolman-Smook JC, Mayosi BM, Brink PA, Corfield VA
  Title
Molecular genetics of cardiomyopathy: changing times, shifting paradigms.
  Journal
Cardiovasc J S Afr 14:145-55 (2003)
Reference
  Authors
Franz WM, Muller OJ, Katus HA
  Title
Cardiomyopathies: from genetics to the prospect of treatment.
  Journal
Lancet 358:1627-37 (2001)
DOI:10.1016/S0140-6736(01)06657-0
Reference
  Authors
Marian AJ, Roberts R
  Title
The molecular genetic basis for hypertrophic cardiomyopathy.
  Journal
J Mol Cell Cardiol 33:655-70 (2001)
DOI:10.1006/jmcc.2001.1340
Reference
PMID:1975517 (MYH7)
  Authors
Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG
  Title
A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation.
  Journal
Cell 62:999-1006 (1990)
DOI:10.1016/0092-8674(90)90274-i
Reference
PMID:11733062 (MYLK2)
  Authors
Davis JS, Hassanzadeh S, Winitsky S, Lin H, Satorius C, Vemuri R, Aletras AH, Wen H, Epstein ND
  Title
The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation.
  Journal
Cell 107:631-41 (2001)
DOI:10.1016/s0092-8674(01)00586-4
Reference
PMID:14672715 (CAV3)
  Authors
Hayashi T, Arimura T, Ueda K, Shibata H, Hohda S, Takahashi M, Hori H, Koga Y, Oka N, Imaizumi T, Yasunami M, Kimura A
  Title
Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy.
  Journal
Biochem Biophys Res Commun 313:178-84 (2004)
DOI:10.1016/j.bbrc.2003.11.101
Reference
PMID:8205619 (TNNT2 TPM1)
  Authors
Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE
  Title
Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.
  Journal
Cell 77:701-12 (1994)
DOI:10.1016/0092-8674(94)90054-x
Reference
PMID:7493025 (MYBPC3)
  Authors
Watkins H, Conner D, Thierfelder L, Jarcho JA, MacRae C, McKenna WJ, Maron BJ, Seidman JG, Seidman CE
  Title
Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy.
  Journal
Nat Genet 11:434-7 (1995)
DOI:10.1038/ng1295-434
Reference
PMID:11371514 (PRKAG2)
  Authors
Blair E, Redwood C, Ashrafian H, Oliveira M, Broxholme J, Kerr B, Salmon A, Ostman-Smith I, Watkins H
  Title
Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis.
  Journal
Hum Mol Genet 10:1215-20 (2001)
DOI:10.1093/hmg/10.11.1215
Reference
PMID:9241277 (TNNI3)
  Authors
Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T, Koyanagi T, Hwang TH, Choo JA, Chung KS, Hasegawa A, Nagai R, Okazaki O, Nakamura H, Matsuzaki M, Sakamoto T, Toshima H, Koga Y, Imaizumi T, Sasazuki T
  Title
Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.
  Journal
Nat Genet 16:379-82 (1997)
DOI:10.1038/ng0897-379
Reference
PMID:8673105 (MYL3 MYL2)
  Authors
Poetter K, Jiang H, Hassanzadeh S, Master SR, Chang A, Dalakas MC, Rayment I, Sellers JR, Fananapazir L, Epstein ND
  Title
Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.
  Journal
Nat Genet 13:63-9 (1996)
DOI:10.1038/ng0596-63
Reference
PMID:10462489 (TTN)
  Authors
Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A
  Title
Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene.
  Journal
Biochem Biophys Res Commun 262:411-7 (1999)
DOI:10.1006/bbrc.1999.1221
Reference
PMID:10330430 (ACTC1)
  Authors
Mogensen J, Klausen IC, Pedersen AK, Egeblad H, Bross P, Kruse TA, Gregersen N, Hansen PS, Baandrup U, Borglum AD
  Title
Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy.
  Journal
J Clin Invest 103:R39-43 (1999)
DOI:10.1172/JCI6460
Reference
PMID:12642359 (CSRP3)
  Authors
Geier C, Perrot A, Ozcelik C, Binner P, Counsell D, Hoffmann K, Pilz B, Martiniak Y, Gehmlich K, van der Ven PF, Furst DO, Vornwald A, von Hodenberg E, Nurnberg P, Scheffold T, Dietz R, Osterziel KJ
  Title
Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy.
  Journal
Circulation 107:1390-5 (2003)
DOI:10.1161/01.cir.0000056522.82563.5f
Reference
PMID:18572189 (TNNC1)
  Authors
Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ
  Title
Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.
  Journal
J Mol Cell Cardiol 45:281-8 (2008)
DOI:10.1016/j.yjmcc.2008.05.003
Reference
PMID:11815426 (MYH6)
  Authors
Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE
  Title
Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.
  Journal
Circulation 105:446-51 (2002)
DOI:10.1161/hc0402.102990
Reference
PMID:16712796 (VCL)
  Authors
Vasile VC, Ommen SR, Edwards WD, Ackerman MJ
  Title
A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy.
  Journal
Biochem Biophys Res Commun 345:998-1003 (2006)
DOI:10.1016/j.bbrc.2006.04.151
Reference
PMID:22987565 (MYOZ2)
  Authors
Ruggiero A, Chen SN, Lombardi R, Rodriguez G, Marian AJ
  Title
Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity.
  Journal
Cardiovasc Res 97:44-54 (2013)
DOI:10.1093/cvr/cvs294
Reference
PMID:17509612 (JPH2)
  Authors
Landstrom AP, Weisleder N, Batalden KB, Bos JM, Tester DJ, Ommen SR, Wehrens XH, Claycomb WC, Ko JK, Hwang M, Pan Z, Ma J, Ackerman MJ
  Title
Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.
  Journal
J Mol Cell Cardiol 42:1026-35 (2007)
DOI:10.1016/j.yjmcc.2007.04.006
Reference
PMID:21167350 (PLN)
  Authors
Landstrom AP, Adekola BA, Bos JM, Ommen SR, Ackerman MJ
  Title
PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing.
  Journal
Am Heart J 161:165-71 (2011)
DOI:10.1016/j.ahj.2010.08.001
Reference
PMID:20970104 (NEXN)
  Authors
Wang H, Li Z, Wang J, Sun K, Cui Q, Song L, Zou Y, Wang X, Liu X, Hui R, Fan Y
  Title
Mutations in NEXN, a Z-disc gene, are associated with hypertrophic cardiomyopathy.
  Journal
Am J Hum Genet 87:687-93 (2010)
DOI:10.1016/j.ajhg.2010.10.002
Reference
PMID:22286171 (MYPN)
  Authors
Purevjav E, Arimura T, Augustin S, Huby AC, Takagi K, Nunoda S, Kearney DL, Taylor MD, Terasaki F, Bos JM, Ommen SR, Shibata H, Takahashi M, Itoh-Satoh M, McKenna WJ, Murphy RT, Labeit S, Yamanaka Y, Machida N, Park JE, Alexander PM, Weintraub RG, Kitaura Y, Ackerman MJ, Kimura A, Towbin JA
  Title
Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
  Journal
Hum Mol Genet 21:2039-53 (2012)
DOI:10.1093/hmg/dds022
Reference
PMID:17097056 (ACTN2 LDB3)
  Authors
Theis JL, Bos JM, Bartleson VB, Will ML, Binder J, Vatta M, Towbin JA, Gersh BJ, Ommen SR, Ackerman MJ
  Title
Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
  Journal
Biochem Biophys Res Commun 351:896-902 (2006)
DOI:10.1016/j.bbrc.2006.10.119
Reference
PMID:15582318 (TCAP)
  Authors
Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Choi BY, Bae SW, You CW, Han KH, Park JE, Knoll R, Hoshijima M, Chien KR, Kimura A
  Title
Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
  Journal
J Am Coll Cardiol 44:2192-201 (2004)
DOI:10.1016/j.jacc.2004.08.058
Reference
PMID:25351925 (FLNC)
  Authors
Valdes-Mas R, Gutierrez-Fernandez A, Gomez J, Coto E, Astudillo A, Puente DA, Reguero JR, Alvarez V, Moris C, Leon D, Martin M, Puente XS, Lopez-Otin C
  Title
Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy.
  Journal
Nat Commun 5:5326 (2014)
DOI:10.1038/ncomms6326
Reference
PMID:28630369 (ALPK3)
  Authors
Caglayan AO, Sezer RG, Kaymakcalan H, Ulgen E, Yavuz T, Baranoski JF, Bozaykut A, Harmanci AS, Yalcin Y, Youngblood MW, Yasuno K, Bilguvar K, Gunel M
  Title
ALPK3 gene mutation in a patient with congenital cardiomyopathy and dysmorphic features.
  Journal
Cold Spring Harb Mol Case Stud 3:a001859 (2017)
DOI:10.1101/mcs.a001859
Reference
PMID:30442288 (FHOD3)
  Authors
Ochoa JP, Sabater-Molina M, Garcia-Pinilla JM, Mogensen J, Restrepo-Cordoba A, Palomino-Doza J, Villacorta E, Martinez-Moreno M, Ramos-Maqueda J, Zorio E, Pena-Pena ML, Garcia-Granja PE, Rodriguez-Palomares JF, Cardenas-Reyes IJ, de la Torre-Carpente MM, Bautista-Paves A, Akhtar MM, Cicerchia MN, Bilbao-Quesada R, Mogollon-Jimenez MV, Salazar-Mendiguchia J, Mesa Latorre JM, Arnaez B, Olavarri-Miguel I, Fuentes-Canamero ME, Lamounier A Jr, Perez Ruiz JM, Climent-Paya V, Perez-Sanchez I, Trujillo-Quintero JP, Lopes LR, Reparaz-Andrade A, Marin-Iglesias R, Rodriguez-Vilela A, Sandin-Fuentes M, Garrote JA, Cortel-Fuster A, Lopez-Garrido M, Fontalba-Romero A, Ripoll-Vera T, Llano-Rivas I, Fernandez-Fernandez X, Isidoro-Garcia M, Garcia-Giustiniani D, Barriales-Villa R, Ortiz-Genga M, Garcia-Pavia P, Elliott PM, Gimeno JR, Monserrat L
  Title
Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy.
  Journal
J Am Coll Cardiol 72:2457-2467 (2018)
DOI:10.1016/j.jacc.2018.10.001
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