RBCC Red Blood Cell Collection

MYLK2 [Confidence: low (only semi-automatic identification from reviews)]
Myosin light chain kinase 2, skeletal/cardiac muscle; MLCK2; 2.7.11.18
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q9H1R3
ID MYLK2_HUMAN Reviewed; 596 AA.
AC Q9H1R3; Q569L1; Q96I84;
DT 19-OCT-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 135.
DE RecName: Full=Myosin light chain kinase 2, skeletal/cardiac muscle;
DE Short=MLCK2;
DE EC=2.7.11.18;
GN Name=MYLK2;
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], FUNCTION, AND VARIANTS CMH VAL-87 AND
RP GLU-95.
RC TISSUE=Skeletal muscle;
RX PubMed=11733062; DOI=10.1016/S0092-8674(01)00586-4;
RA Davis J.S., Hassanzadeh S., Winitsky S., Lin H., Satorius C.,
RA Vemuri R., Aletras A.H., Wen H., Epstein N.D.;
RT "The overall pattern of cardiac contraction depends on a spatial
RT gradient of myosin regulatory light chain phosphorylation.";
RL Cell 107:631-641(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Skeletal muscle;
RA Stanchi F., Lanfranchi G.;
RT "Full-length sequencing of 100 cDNA clones from human adult skeletal
RT muscle.";
RL Submitted (FEB-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 566-587 IN COMPLEX WITH
RP CENTRIN, AND SUBUNIT.
RA Radu L., Miron S., Durand D., Assairi L., Blouquit Y.,
RA Charbonnier J.B.;
RT "Structural features of the complexes formed by Scherffelia dubia
RT centrin.";
RL Submitted (JAN-2011) to the PDB data bank.
RN [6]
RP VARIANTS [LARGE SCALE ANALYSIS] VAL-117; VAL-142; ALA-144 AND ASN-324.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Implicated in the level of global muscle contraction and
CC cardiac function. Phosphorylates a specific serine in the N-
CC terminus of a myosin light chain.
CC -!- CATALYTIC ACTIVITY: ATP + [myosin light-chain] = ADP + [myosin
CC light-chain] phosphate.
CC -!- SUBUNIT: May interact with centrin.
CC -!- INTERACTION:
CC Q06413:MEF2C; NbExp=2; IntAct=EBI-356910, EBI-2684075;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=Colocalizes with
CC phosphorylated myosin light chain (RLCP) at filaments of the
CC myofibrils.
CC -!- TISSUE SPECIFICITY: Heart and skeletal muscles. Increased
CC expression in the apical tissue compared to the interventricular
CC septal tissue.
CC -!- DISEASE: Cardiomyopathy, familial hypertrophic (CMH) [MIM:192600]:
CC A hereditary heart disorder characterized by ventricular
CC hypertrophy, which is usually asymmetric and often involves the
CC interventricular septum. The symptoms include dyspnea, syncope,
CC collapse, palpitations, and chest pain. They can be readily
CC provoked by exercise. The disorder has inter- and intrafamilial
CC variability ranging from benign to malignant forms with high risk
CC of cardiac failure and sudden cardiac death. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK
CC Ser/Thr protein kinase family.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
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DR EMBL; AF325549; AAK15494.1; -; mRNA.
DR EMBL; AJ272502; CAC81354.1; -; mRNA.
DR EMBL; AL160175; CAC10006.1; -; Genomic_DNA.
DR EMBL; BC007753; AAH07753.1; -; mRNA.
DR EMBL; BC069627; AAH69627.1; -; mRNA.
DR EMBL; BC092413; AAH92413.1; -; mRNA.
DR EMBL; BC127622; AAI27623.1; -; mRNA.
DR RefSeq; NP_149109.1; NM_033118.3.
DR UniGene; Hs.86092; -.
DR PDB; 2LV6; Other; -; B=566-591.
DR PDB; 3KF9; X-ray; 2.60 A; B/D=566-587.
DR PDBsum; 2LV6; -.
DR PDBsum; 3KF9; -.
DR ProteinModelPortal; Q9H1R3; -.
DR SMR; Q9H1R3; 261-591.
DR IntAct; Q9H1R3; 7.
DR MINT; MINT-1158812; -.
DR STRING; 9606.ENSP00000365152; -.
DR BindingDB; Q9H1R3; -.
DR ChEMBL; CHEMBL2777; -.
DR GuidetoPHARMACOLOGY; 1553; -.
DR PhosphoSite; Q9H1R3; -.
DR DMDM; 24211884; -.
DR PaxDb; Q9H1R3; -.
DR PRIDE; Q9H1R3; -.
DR DNASU; 85366; -.
DR Ensembl; ENST00000375985; ENSP00000365152; ENSG00000101306.
DR Ensembl; ENST00000375994; ENSP00000365162; ENSG00000101306.
DR GeneID; 85366; -.
DR KEGG; hsa:85366; -.
DR UCSC; uc002wwq.2; human.
DR CTD; 85366; -.
DR GeneCards; GC20P030407; -.
DR HGNC; HGNC:16243; MYLK2.
DR MIM; 192600; phenotype.
DR MIM; 606566; gene.
DR neXtProt; NX_Q9H1R3; -.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR PharmGKB; PA31389; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233016; -.
DR HOVERGEN; HBG080416; -.
DR InParanoid; Q9H1R3; -.
DR KO; K00907; -.
DR OMA; EGVPMTH; -.
DR OrthoDB; EOG73FQMV; -.
DR BRENDA; 2.7.11.18; 2681.
DR SignaLink; Q9H1R3; -.
DR EvolutionaryTrace; Q9H1R3; -.
DR GeneWiki; MYLK2; -.
DR GenomeRNAi; 85366; -.
DR NextBio; 75899; -.
DR PRO; PR:Q9H1R3; -.
DR Bgee; Q9H1R3; -.
DR CleanEx; HS_MYLK2; -.
DR Genevestigator; Q9H1R3; -.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0030017; C:sarcomere; IC:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005516; F:calmodulin binding; ISS:BHF-UCL.
DR GO; GO:0004683; F:calmodulin-dependent protein kinase activity; ISS:BHF-UCL.
DR GO; GO:0004687; F:myosin light chain kinase activity; IDA:BHF-UCL.
DR GO; GO:0055007; P:cardiac muscle cell differentiation; IEA:Ensembl.
DR GO; GO:0060048; P:cardiac muscle contraction; IC:BHF-UCL.
DR GO; GO:0055008; P:cardiac muscle tissue morphogenesis; IMP:BHF-UCL.
DR GO; GO:0007274; P:neuromuscular synaptic transmission; IEA:Ensembl.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0032971; P:regulation of muscle filament sliding; IDA:BHF-UCL.
DR GO; GO:0014816; P:satellite cell differentiation; IEA:Ensembl.
DR GO; GO:0035914; P:skeletal muscle cell differentiation; IDA:UniProtKB.
DR InterPro; IPR020636; Ca/CaM-dep_Ca-dep_prot_Kinase.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR24347; PTHR24347; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Calmodulin-binding;
KW Cardiomyopathy; Complete proteome; Cytoplasm; Disease mutation;
KW Kinase; Nucleotide-binding; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 596 Myosin light chain kinase 2,
FT skeletal/cardiac muscle.
FT /FTId=PRO_0000086408.
FT DOMAIN 285 540 Protein kinase.
FT NP_BIND 291 299 ATP (By similarity).
FT REGION 574 586 Calmodulin-binding (By similarity).
FT COMPBIAS 261 268 Poly-Pro.
FT ACT_SITE 406 406 Proton acceptor (By similarity).
FT BINDING 314 314 ATP (By similarity).
FT MOD_RES 2 2 N-acetylalanine (By similarity).
FT VARIANT 87 87 A -> V (in CMH; dbSNP:rs121908107).
FT /FTId=VAR_014197.
FT VARIANT 95 95 A -> E (in CMH; dbSNP:rs121908108).
FT /FTId=VAR_014198.
FT VARIANT 117 117 A -> V (in a lung neuroendocrine
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040860.
FT VARIANT 142 142 G -> V (in dbSNP:rs56385445).
FT /FTId=VAR_040861.
FT VARIANT 144 144 P -> A (in dbSNP:rs34396614).
FT /FTId=VAR_040862.
FT VARIANT 324 324 K -> N (in dbSNP:rs34146416).
FT /FTId=VAR_040863.
FT CONFLICT 355 361 IVLFMEY -> GGVCAHS (in Ref. 4; AAH07753).
FT HELIX 567 586
SQ SEQUENCE 596 AA; 64685 MW; 671A2B5DE9453ADE CRC64;
MATENGAVEL GIQNPSTDKA PKGPTGERPL AAGKDPGPPD PKKAPDPPTL KKDAKAPASE
KGDGTLAQPS TSSQGPKGEG DRGGGPAEGS AGPPAALPQQ TATPETSVKK PKAEQGASGS
QDPGKPRVGK KAAEGQAAAR RGSPAFLHSP SCPAIISSSE KLLAKKPPSE ASELTFEGVP
MTHSPTDPRP AKAEEGKNIL AESQKEVGEK TPGQAGQAKM QGDTSRGIEF QAVPSEKSEV
GQALCLTARE EDCFQILDDC PPPPAPFPHR MVELRTGNVS SEFSMNSKEA LGGGKFGAVC
TCMEKATGLK LAAKVIKKQT PKDKEMVLLE IEVMNQLNHR NLIQLYAAIE TPHEIVLFME
YIEGGELFER IVDEDYHLTE VDTMVFVRQI CDGILFMHKM RVLHLDLKPE NILCVNTTGH
LVKIIDFGLA RRYNPNEKLK VNFGTPEFLS PEVVNYDQIS DKTDMWSMGV ITYMLLSGLS
PFLGDDDTET LNNVLSGNWY FDEETFEAVS DEAKDFVSNL IVKDQRARMN AAQCLAHPWL
NNLAEKAKRC NRRLKSQILL KKYLMKRRWK KNFIAVSAAN RFKKISSSGA LMALGV
//

MIM 192600
*RECORD*
*FIELD* NO
192600
*FIELD* TI
#192600 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1; CMH1
;;CMH;;
VENTRICULAR HYPERTROPHY, HEREDITARY;;
read moreASYMMETRIC SEPTAL HYPERTROPHY; ASH;;
HYPERTROPHIC SUBAORTIC STENOSIS, IDIOPATHIC
*FIELD* TX
A number sign (#) is used with this entry because hypertrophic
cardiomyopathy-1 (CMH1) is caused by heterozygous mutation in the MYH7
gene (160760) on chromosome 14q12.

DESCRIPTION

Hereditary ventricular hypertrophy (CMH, HCM, ASH, or IHSS) in early
stages produces a presystolic gallop due to an atrial heart sound, and
EKG changes of ventricular hypertrophy. Progressive ventricular outflow
obstruction may cause palpitation associated with arrhythmia, congestive
heart failure, and sudden death. Seidman (2000) reviewed studies of
hypertrophic cardiomyopathy in man and mouse.

- Genetic Heterogeneity of Hypertrophic Cardiomyopathy

Additional forms of hypertrophic cardiomyopathy include CMH2 (115195),
caused by mutation in the TNNT2 gene (191045) on chromosome 1q32; CMH3
(115196), caused by mutation in the TPM1 gene (191010) on chromosome
15q22.1; CMH4 (115197), caused by mutation in the MYBPC3 gene (600958)
on chromosome 11p11.2; CMH6 (600858), caused by mutation in the PRKAG2
gene (602743) on chromosome 7q36; CMH7 (613690), caused by mutation in
the TNNI3 gene (191044) on chromosome 19q13.4; CMH8 (608751), caused by
mutation in the MYL3 gene (160790) on chromosome 3p21.3-p21.2; CMH9 (see
188840),is caused by mutation in the TTN gene (188840) on chromosome
2q31; CMH10 (see 160781), caused by mutation in the MYL2 gene (160781)
on chromosome 12q23-q24; CMH11 (612098), caused by mutation in the ACTC1
gene (102540) on chromosome 15q14; CMH12 (612124), caused by mutation in
the CSRP3 gene (600824) on chromosome 11p15.1; CMH13 (613243), caused by
mutation in the TNNC1 gene (191040) on chromosome 3p21.3-p14.3; CMH14
(613251), caused by mutation in the MYH6 gene (160710) on chromosome
14q12; CMH15 (613255), caused by mutation in the VCL gene (193065) on
chromosome 10q22.1-q23; CMH16 (613838), caused by mutation in the MYOZ2
gene (605602) on chromosome 4q26-q27; CMH17 (613873), caused by mutation
in the JPH2 gene (605267) on chromosome 20q12; CMH18 (613874), caused by
mutation in the PLN gene (172405) on chromosome 6q22.1; CMH19 (613875),
caused by mutation in the CALR3 gene (611414) on chromosome 19p13.11;
CMH20 (613876), caused by mutation in the NEXN gene (613121) on
chromosome 1p31.1; CMH21, mapped to chromosome 7p12.1-q21; and CMH22
(see 615248), caused by mutation in the MYPN gene (608517) on chromosome
10q21.

The CMH5 designation was initially assigned to a CMH family showing
genetic heterogeneity. Subsequently, affected individuals were found to
carry mutations in the MYH7 (CMH1) and/or MYBPC3 (CMH4) genes.

Hypertrophic cardiomyopathy has also been associated with mutation in
the gene encoding cardiac myosin light-peptide kinase (MYLK2; see
606566.0001), which resides on chromosome 20q13.3; the gene encoding
caveolin-3 (CAV3; see 601253.0013), which maps to chromosome 3p25; and
with mutations in genes encoding mitochondrial tRNAs: see mitochondrial
tRNA-glycine (MTTG; 590035) and mitochondrial tRNA-isoleucine (MTTI;
590045).

CLINICAL FEATURES

In the first demonstration of asymmetric hypertrophy of the heart in
young adults, Teare (1958) reported the autopsy findings in 9 cases of
sudden death in young subjects distributed in 6 families. This condition
has been called muscular subaortic stenosis but more generalized
ventricular hypertrophy is often an earlier and more impressive feature,
and obstruction to outflow from the right ventricle can also occur.
Study of the families of probands with the full-blown condition shows
that an atrial heart sound ('presystolic gallop') and EKG changes of
ventricular hypertrophy are the earliest signs. Sudden death occurs in
some cases. Braunwald et al. (1964) reported in detail on 64 patients;
multiple cases were observed in 11 families, which contained in all at
least 41 definite or probable cases. As pointed out by Nasser et al.
(1967), outflow obstruction may be absent in some affected members of
families in which others do have outflow obstruction. Maron et al.
(1974) studied 4 infants that died with ASH in the first 5 months of
life, including 1 stillborn. ASH was demonstrated in one first-degree
relative of each infant. Maron et al. (1976) analyzed the clinical
picture of 46 children with ASH. On the basis of a study of an
outpatient population, Spirito et al. (1989) suggested that the
prognosis in hypertrophic cardiomyopathy may be less grave than has
usually been considered on the basis of hospital-study patients.

On morphologic grounds, 4 types of hypertrophic cardiomyopathy have been
described: type 1 with hypertrophy confined to the anterior segment of
the ventricular septum; type 2 with hypertrophy of both the anterior and
the posterior segments of the ventricular septum; type 3 with
involvement of both the ventricular septum and the free wall of the left
ventricle and type 4 with involvement of the posterior segment of the
septum, the anterolateral free wall, or the apical half of the septum
(Maron et al., 1982; Ciro et al., 1983). Apical hypertrophic
cardiomyopathy is, therefore, one form of type IV. It was first
described by Yamaguchi et al. (1979) in Japan (where it appears to be
more frequent than elsewhere) and later by Maron et al. (1982). The
cases of apical hypertrophic cardiomyopathy described by Maron et al.
(1982) belonged to families with different forms of hypertrophic
cardiomyopathy. Malouf et al. (1985) reported apical hypertrophic
cardiomyopathy in father and daughter of a Lebanese Christian family.
The parents were not related; an only sib was normal on examination and
echocardiogram as were 2 sisters of the father and their 6 children.

In a metaanalysis of sudden death from cardiac causes in children and
young adults, Liberthson (1996) found that hypertrophic cardiomyopathy
was the most frequent cause of sudden death in young persons in
association with strenuous physical exertion or sports.

OTHER FEATURES

Maron et al. (1996) collected information on 158 sudden deaths that had
occurred in trained athletes throughout the United States from 1985
through 1995. In 24 athletes (15%), noncardiovascular causes were found.
Among the 134 athletes who had cardiovascular causes of sudden death,
the median age was 17 years. The most common competitive sports involved
were basketball (47 cases) and football (45 cases), together accounting
for 68% of sudden deaths. The most common structural cardiovascular
diseases identified at autopsy as the primary cause of death were
hypertrophic cardiomyopathy (48 athletes, 36%), which was
disproportionately prevalent in black athletes compared with white
athletes (48% vs 26% of deaths; P = 0.01), and malformations involving
anomalous coronary artery origin (17 athletes, 13%). Of 115 athletes who
had a standard preparticipation medical evaluation, only 4 (3%) were
suspected of having cardiovascular disease, and the cardiovascular
anomaly responsible for sudden death was correctly identified in only 1
athlete (0.9%).

In a series of 387 young athletes who died suddenly, Maron (2003) found
that hypertrophic cardiomyopathy was the cause in 102 (26.4%). Coronary
artery anomalies had accounted for 53 (13.7%) and ruptured aortic
aneurysm of Marfan syndrome for 12 (3.1%). Arrhythmogenic right
ventricular cardiomyopathy was found in 11 (2.8%) and long QT syndrome
in 3 (0.8%).

Cannon (2003) tabulated the features of hypertrophic cardiomyopathy that
increase the risk of cardiovascular events. These included family
history of sudden death, recurrent syncope, ventricular tachycardia on
monitoring, extreme left ventricular hypertrophy (more than 3 cm), left
ventricular outflow pressure gradient of more than 30 mm Hg, and fall in
blood pressure during exercise.

INHERITANCE

In the family reported by Horlick et al. (1966), 10 persons in 4
generations were thought to have been affected. Pare et al. (1961)
described this disorder in 30 out of 87 members of a French Canadian
kindred. The genealogic survey was carried back to the original emigrant
from France in the 1600s. The pattern of occurrence over 5 generations
and 160 years since the death of the man believed to be the first
instance of the heart disease indicated autosomal dominant inheritance.
Elevated paternal age of sporadic (possible fresh mutation) cases was
observed by Jorgensen (1968). The family study of Clark et al. (1973),
using echocardiography, indicated that 28 of 30 probands (93%) had an
affected parent. This agrees well with estimates of the extent to which
this disorder, on the average, reduces reproductive fitness.

Greaves et al. (1987) performed echocardiographic studies of 193
first-degree relatives of 50 patients with hypertrophic cardiomyopathy.
More males than females were affected. In 28 of 50 families, familial
occurrence was observed. In 15 families the pattern of inheritance was
consistent with autosomal dominant inheritance; in the other 13 the
affected members were in a single generation and the pattern of
inheritance could not be determined.

The family reported by Yamaguchi et al. (1979) suggested X-linked
recessive inheritance. Burn (1985) felt that the existence of a
recessive form of hypertrophic cardiomyopathy (Emanuel et al., 1971;
Branzi et al., 1985) could neither be established nor disproved at the
time of his writing. Branzi et al. (1985) claimed the existence of an
autosomal recessive form because of a family they found with 2 affected
sisters and both parents normal by careful study. Formal segregation
analysis supported the existence of 2 classes: one with a segregation
ratio close to 50% and one with a value close to 25%.

MAPPING

Darsee et al. (1979) found a lod score of 7.7 for linkage between ASH
and HLA. They concluded that, in addition to the hereditary form linked
to HLA, a sporadic unlinked form is associated with severe systemic
hypertension. White patients with ASH were B12; black patients were B5.
This presumably strong evidence placing a gene for hypertrophic
subaortic stenosis on 6p by linkage to HLA was invalidated when the
infamous John R. Darsee confessed fabrication of the data. Nutter also
published a retraction. Motulsky (1979) wrote a laudatory editorial to
accompany the original article.

In his retraction letter, Darsee stated: 'The lod scores were
calculated, in part, by one of the journal referees who felt they should
be included, and partly by my own calculations. The biometrist I
consulted at Emory regarding these calculations was not familiar with
lod scores and unable to provide assistance.' Before Darsee confessed,
Darsee and Heymsfield (1981) wrote: 'It is the pinhole through which we
are forced to view this disease or these diseases that has helped confer
a degree of homogeneity. The pinhole is the limited collection of tools
we have to study hypertrophic cardiomyopathy--the angiogram, the
echocardiogram, and the autopsy table. It is a common practice of even
the most perspicacious and critical investigators to conclude that
diseases that look the same on canvas were painted with the same brush.'
Although these words are true in general terms and are a fine statement
of the principle of genetic heterogeneity, the falsified data do not
support them, of course.

Jarcho et al. (1989) did studies with DNA markers in the Canadian family
originally reported by Pare et al. (1961). At the time of the study,
hypertrophic cardiomyopathy had occurred in 20 surviving and 24 deceased
family members. With a polymorphic DNA probe with the trivial name
CRI-L436, which identified a DNA segment designated D14S26, they found
no recombination (lod score = 9.37 at theta = 0). This probe had been
assigned to chromosome 14 on the basis of somatic cell hybrid analysis
(Donis-Keller et al., 1987). The gene encoding the alpha chain of the
T-cell receptor (see 186880) was located approximately 20 cM from D14S26
(Mitchell et al., 1989). Solomon et al. (1990) mapped the probe CRI-L436
to 14q11-q12 by in situ hybridization. Because the cardiac myosin heavy
chain genes (MYH6, 160710; MYH7) map to the same chromosomal band, they
determined the genetic distance between the gene for the beta heavy
chain of cardiac myosin, D14S26, and the CMH1 locus. They presented data
indicating that these 3 loci are linked within 5 cM of each other. The
data were consistent with the possibility that the CMH1 mutation is in
either the alpha or the beta gene.

Hejtmancik et al. (1991) found that the gene for familial hypertrophic
cardiomyopathy was located at 14q1 in 8 unrelated families of varied
ethnic origins. Of 5 families with hypertrophic cardiomyopathy, Epstein
et al. (1992) found linkage to chromosome 14 markers in one and
suggestive linkage in a second. However, linkage to chromosome 14
markers was excluded in the other 3 kindreds. Ko et al. (1992) excluded
linkage to D14S26 in a Chinese family, likewise indicating genetic
heterogeneity.

MOLECULAR GENETICS

In affected members of the large French Canadian kindred originally
reported by Pare et al. (1961) and shown to have linkage to markers on
the proximal portion of 14q, Geisterfer-Lowrance et al. (1990)
identified heterozygosity for a missense mutation in the MYH7 gene
(R403Q; 160760.0001). Ross and Knowlton (1992) reviewed this discovery
beginning with the patients first seen by Pare in the 1950s.

Using a ribonuclease protection assay, Watkins et al. (1992) screened
the beta cardiac myosin heavy-chain genes of probands from 25 unrelated
families with familial hypertrophic cardiomyopathy and identified 7
different missense mutations in 12 of the 25 families (see, e.g.,
160760.0003-160760.0007).

Atiga et al. (2000) studied 36 patients with CMH1 using beat-to-beat QT
variability analysis. This technique quantifies the beat-to-beat
fluctuations in ventricular repolarization reflected in the QT interval.
Seven mutations were found in this group: 9 patients had the 'severe'
arg403-to-gln mutation (160760.0001) and 8 had the more benign
leu908-to-val mutation (160760.0010). Atiga et al. (2000) found higher
QT variability indices in patients with CMH1 compared with controls, and
the greatest abnormality was observed in patients with the arg403-to-gln
mutation. CMH1 patients therefore exhibited labile ventricular
repolarization and were considered to be at higher risk of sudden death
from ventricular arrhythmias, particularly those with a 'severe'
mutation.

Blair et al. (2001) studied a family with familial hypertrophic
cardiomyopathy in which 2 individuals suffered early sudden death and a
third individual died suddenly at the age of 60 years with autopsy
evidence of familial hypertrophic cardiomyopathy. A val606-to-met
(V606M) mutation was observed in the MYH7 gene (160760.0005). This
mutation had previously been proposed to give rise to a benign phenotype
(see Abchee and Marian, (1997)). A second ala728-to-val (A728V) mutation
(160760.0025) was found in cis with the V606M mutation. Blair et al.
(2001) suggested that this second mutation in cis explained the more
severe phenotype seen in this family.

Arad et al. (2005) identified 2 different MYH7 missense mutations in 2
probands with apical hypertrophy from families in which the mutations
also caused other CMH morphologies (see 160760.0038 and 160760.0039,
respectively). Another MYH7 mutation (R243H; 160760.0040) was identified
in a sporadic patient with apical hypertrophy; the same R243H mutation
was later found by Klaassen et al. (2008) in a family segregating
isolated left ventricular noncompaction (LVNC5; see 613426).

In a Japanese proband with CMH (CMH17; 613873), Matsushita et al. (2007)
identified heterozygosity for a missense mutation in the JPH2 gene
(605267.0004); subsequent analysis of 15 known CMH-associated genes
revealed that the proband also carried 2 mutations in MYH7 (see, e.g.,
160760.0016). The authors suggested that mutations in both JPH2 and MYH7
could be associated with the pathogenesis of CMH in this proband.

In a 32-year-old African American woman with severe hypertrophic
cardiomyopathy (see CMH7, 613690) and a family history of CMH and sudden
cardiac death, Frazier et al. (2008) identified a heterozygous mutation
in the TNNI3 gene (P82S; 191044.0003) and a heterozygous mutation in the
MYH7 gene (R453S; 160760.0043). Frazier et al. (2008) suggested that the
P82S variant, which they found in 3% of healthy African Americans, is a
disease-modifying mutation in severely affected individuals, and that
carriers of the variant might be at increased risk of late-onset cardiac
hypertrophy.

- Skeletal Muscle Involvement

Fananapazir et al. (1993) demonstrated by biopsy of the soleus muscle
the presence of central core disease of skeletal muscle (117000) in
association with hypertrophic cardiomyopathy due to any of 4 different
mutations in the MYH7 gene. Soleus muscle samples from patients in 4
kindreds in which hypertrophic cardiomyopathy was not linked to the MYH7
locus showed no myopathy or central core disease. In 1 family with the
leu908-to-val mutation of the MYH7 gene (160760.0010), central core
disease was demonstrated on soleus muscle biopsy, although cardiac
hypertrophy was absent on echocardiogram in 2 adults and 3 children.
Almost all patients had no significant muscle weakness, despite the
histologic changes. The histologic hallmark of CCD was the absence of
mitochondria in the center of many type I fibers as revealed by light
microscopic examination of NADH-stained fresh-frozen skeletal muscle
sections. McKenna (1993), who stated that he had never seen clinical
evidence of skeletal myopathy in CMH1, doubted the significance of the
findings.

In a 44-year-old male with hypertrophic cardiomyopathy and respiratory
failure, born of second-cousin British parents, Tajsharghi et al. (2007)
identified homozygosity for a missense mutation in the MYH7 gene
(E1883K; 160760.0035). The proband had 2 similarly affected sibs, a
sister who had died at 57 years of age in cardiorespiratory failure and
a brother who died at age 32 years from cardiac failure. Muscle biopsies
from all 3 sibs showed findings typical for myosin storage myopathy
(608358) with hyaline bodies seen in type 1 fibers. The sister had
progressive muscle weakness and was wheelchair dependent by age 45,
whereas the 2 brothers had milder proximal muscle weakness. The
unaffected parents were presumed heterozygous carriers of the mutation,
and another sib was unaffected. There was no family history of muscle
weakness.

In a mother with myosin storage myopathy, who later developed CMH, and
in her daughter, who had early-symptomatic left ventricular
noncompaction (LVNC5; see 613426), Uro-Coste et al. (2009) identified
heterozygosity for the L1793P mutation in MYH7 (160760.0037). The mother
presented at age 30 years with proximal muscle weakness, which
progressed to the point of her being wheelchair-bound by 48 years of
age. At age 51, CMH was diagnosed; echocardiography revealed no atrial
or ventricular dilatation, and no abnormal appearance of the ventricular
walls. Skeletal muscle biopsy at 53 years of age showed subsarcolemmal
accumulation of hyaline material in type 1 fibers. Her 24-year-old
daughter presented with heart failure at 3 months of age and was
diagnosed with early-onset cardiomyopathy. Angiography revealed a
less-contractile, irregular 'spongiotic' wall in the inferior left
ventricle, and echocardiography confirmed the diagnosis of LVNC. The
daughter did not complain of muscle weakness, but clinical examination
revealed bilateral wasting of the distal leg anterior compartment and
she had some difficulty with heel-walking.

HETEROGENEITY

In affected members of an Italian family, Ferraro et al. (1990) found
that 7 affected members and none of 3 unaffected members showed a
fragile site on 16q (FRA16B).

Hengstenberg et al. (1993, 1994) studied a family with familial
hypertrophic cardiomyopathy in which preliminary haplotype analyses
excluded linkage to chromosomes 14q1, 1q3, 11p13-q13, and 15q2,
suggesting the existence of another locus, designated CMH5, for this
disorder. Further studies in this family by Richard et al. (1999)
demonstrated that of 8 affected family members, 4 had a mutation in the
MYH7 gene (160760.0033), 2 had a mutation in the MYBPC3 gene
(600958.0014), and 2 were doubly heterozygous for the 2 mutations. The
doubly heterozygous patients exhibited marked left ventricular
hypertrophy, which was significantly greater than that in the other
affected individuals.

Seidman and Seidman (2001) reviewed the genetic and clinical
heterogeneity of hypertrophic cardiomyopathy.

Arad et al. (2002) reviewed the clinical spectrum of hypertrophic
cardiomyopathy in the context of genetic heterogeneity, as well as
animal models of hypertrophic cardiomyopathy.

In 108 consecutive patients with hypertrophic cardiomyopathy diagnosed
by echocardiography, angiography, or findings after myectomy, Erdmann et
al. (2003) screened for mutations in 6 sarcomeric genes. They identified
34 different mutations: 18 in the MYBPC3 gene in 20 patients, with 2
mutations identified twice; 13 missense mutations in the MYH7 gene in 14
patients, with 1 mutation identified twice; and 1 amino acid change each
in the TPM1, TNNT2, and TNNI3 genes. No disease-causing mutation was
identified in TNNC1 (191040). In only 8 of the 37 mutation carriers was
the mutation sporadic. Thus, systematic mutation screening in a large
sample of patients with hypertrophic cardiomyopathy led to a genetic
diagnosis in approximately 30% of unrelated index patients and in
approximately 57% of patients with a positive family history.

In 197 unrelated probands with familial or sporadic hypertrophic
cardiomyopathy, Richard et al. (2003) screened for mutations in 9 genes
and identified mutations in 124 (63%) of 197 probands. The MYBPC3 and
MYH7 genes accounted for 82% of families with identified mutations (42%
and 40%, respectively). A mutation was identified in 15 (60%) of 25
sporadic patients.

In 80 unrelated Australian probands with CMH, Chiu et al. (2007)
screened 7 CMH genes, including MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, MYL2,
and MYL3. Twenty-four different mutations were identified in 23 (29%) of
80 families, with 19 probands having a single mutation (11 in MYH7, 4 in
MYPBC3, 3 in TNNI3, and 1 in TNNT2). Multiple gene mutations were
identified in 4 probands: 1 was doubly heterozygous, with 1 mutation in
MYH7 and 1 in MYBPC3, whereas the other 3 were compound heterozygous for
mutations in MYBPC3 (see, e.g., 600958.0021 and 600958.0022). Six (43%)
of 14 affected individuals from multiple mutation families experienced
sudden cardiac death, compared with 10 (18%) of 55 affected members from
single mutation families (p = 0.05). Septal wall thickness was increased
in patients with multiple mutations (mean thickness, 30.7 mm vs 24.4 mm;
p less than 0.05). Ingles et al. (2005) concluded that multiple gene
mutations occurring in CMH families may result in a more severe clinical
phenotype because of a 'double-dose' effect, and emphasized the
importance of screening the entire panel of CMH genes even after a
single mutation has been identified.

Van Driest et al. (2004) analyzed the MYBPC3 gene in a cohort of 389 CMH
probands who had previously been genotyped for mutation in genes
encoding the sarcomeric proteins comprising the thick filament (MYH7 and
the regulatory and essential light chains, MYL2 and MYL3) and the thin
filament (TNNT2, TNNI3, TPM1, and ACTC). Overall, 63 (16.2%) of the
patients had a single mutation in the MYBPC3 gene, 54 (13.8%) in MYH7, 7
(1.8%) in MYL2, 6 (1.5%) in TNNT2, 4 (1.0%) in TNNI3, 2 (0.5%) in TPM1,
and 1 (0.3%) in ACTC. The 10 patients with multiple mutations (2.6%) had
the most severe disease presentation: they were significantly younger at
diagnosis than any other subgroup, had the most hypertrophy, and had the
highest incidence of myectomy and placement of implantable
cardioverter-defibrillators.

DIAGNOSIS

To screen for mutations that cause familial hypertrophic cardiomyopathy,
Rosenzweig et al. (1991) capitalized on the fact that 'ectopic' or
'illegitimate' transcription of beta cardiac myosin heavy chain gene can
be detected in blood lymphocytes. Preclinical or prenatal screening will
make it possible to study the disorder longitudinally and to develop
preventive interventions. The findings again illustrate the important
application of PCR. Clarke and Harper (1992) suggested that 'the
parallels between this cardiomyopathy and Huntington's disease are
sufficiently striking that we would be very cautious about testing for
it in childhood. The emotional consequences of being brought up under a
cloud of doom may be damaging, and the lack of any uncertainty in
identifying gene carriers by mutation analysis might paradoxically make
this worse.' Watkins et al. (1992) countered this view, saying that
children with the condition face a 4 to 6% risk of sudden death each
year. Genetic diagnosis will allow evaluation of prophylactic use of
antiarrhythmic agents or implantable defibrillator devices. It will also
provide parents and physicians an appropriate basis on which to make
decisions regarding the participation of children in competitive sports.
They suggested that in their experience '...any perception of a cloud of
doom comes as much from a lack of knowledge of and research into this
inherited cardiomyopathy as from anything else.'

To provide a method of genetic diagnosis of cardiomyopathy, Mogensen et
al. (2001) developed a method of linkage analysis using multiplex PCR of
markers covering 9 loci associated with familial hypertrophic
cardiomyopathy. They evaluated this method in 3 families. In all 3
families the locus showing the highest lod score was subsequently found
by mutation analysis to be the locus at which the disease-causing gene
was found. Mogensen et al. (2001) emphasized the importance of stringent
phenotypic definitions in the diagnostic process.

Ingles et al. (2013) studied the clinical predictors of genetic testing
outcomes for hypertrophic cardiomyopathy. The authors studied 265
unrelated individuals with hypertrophic cardiomyopathy over a 10-year
period in specialized cardiac genetic clinics across Australia. Of the
265 individuals studied, 138 (52%) had at least 1 mutation identified.
The mutation detection rate was significantly higher in probands with
hypertrophic cardiomyopathy with an established family history of
disease (72% vs 29%, p less than 0.0001), and a positive family history
of sudden cardiac death further increased the detection rate (89% vs
59%, p less than 0.0001). Multivariate analysis identified female
gender, increased left ventricular wall thickness, family history of
hypertrophic cardiomyopathy, and family history of sudden cardiac death
as being associated with greatest chance of identifying a gene mutation.
Multiple mutation carriers (n = 16, 6%) were more likely to have
suffered an out-of-hospital cardiac arrest or sudden cardiac death (31%
vs 7%, p = 0.012). Ingles et al. (2013) concluded that family history is
a key clinical predictor of a positive genetic diagnosis and has direct
clinical relevance, particularly in the pretest genetic counseling
setting.

PATHOGENESIS

Wagner et al. (1989) investigated a possible role of adrenergic
innervation or of cellular calcium regulation in pathogenesis, as
suggested by the presence of hyperdynamic left ventricular function and
by the clinical and symptomatic improvement seen in patients treated
with beta-receptor antagonists or calcium antagonists. They found that
calcium-antagonist binding sites, measured as the amount of
dihydropyridine bound to atrial tissue, were increased by 33% in
patients with hypertrophic cardiomyopathy. The densities of
saxitoxin-binding sites on voltage-sensitive sodium channels and
beta-adrenoceptors did not differ from controls. Wagner et al. (1989)
interpreted the findings as suggesting that abnormal calcium fluxes
through voltage-sensitive calcium channels may play a pathophysiologic
role in the disease.

There is evidence that 'myocardial bridging' with compression of an
epicardial coronary artery, such as the left anterior descending
coronary artery, can cause myocardial ischemia and sudden death. Yetman
et al. (1998) performed angiographic studies of 36 children with
hypertrophic cardiomyopathy to determine whether myocardial bridging was
present and, if so, to assess the characteristics of systolic narrowing
of the left anterior descending coronary artery caused by myocardial
bridging and the duration of residual diastolic compression. Myocardial
bridging was present in 10 (28%) of the patients. As compared with
patients without bridging, patients with bridging had a greater
incidence of chest pain, cardiac arrest with subsequent resuscitation,
and ventricular tachycardia. On average, the patients with bridging had
a reduction in systolic blood pressure with exercise, as compared with
an elevation in those without bridging. Patients with bridging also had
greater ST-segment depression with exercise and a shorter duration of
exercise. Kaplan-Meier estimates of the proportions of patients who had
not died or had cardiac arrest with subsequent resuscitation 5 years
after the diagnosis of hypertrophic cardiomyopathy were 67% among
patients with bridging and 94% among those without bridging. No
statement concerning the family history or other information relevant to
a etiology in these patients was provided.

Using pharmacologic models of cardiac hypertrophy in mice, Friddle et
al. (2000) performed expression profiling with fragments of more than
4,000 genes to characterize and contrast expression changes during
induction and regression of hypertrophy. Administration of angiotensin
II and isoproterenol by osmotic minipump produced increases in cardiac
weight (15% and 45%, respectively) that returned to preinduction size
after drug withdrawal. From multiple expression analyses of left
ventricular RNA isolated at daily time points during cardiac hypertrophy
and regression, Friddle et al. (2000) identified sets of genes whose
expression was altered at specific stages of this process. While
confirming the participation of 25 genes or pathways previously shown to
be altered by hypertrophy, a larger set of 30 genes was identified whose
expression had not previously been associated with cardiac hypertrophy
or regression. Of the 55 genes that showed reproducible changes during
the time course of induction and regression, 32 were altered only during
induction, and 8 were altered only during regression. Thus, cardiac
remodeling during regression uses a set of genes that are distinct from
those used during induction of hypertrophy.

Tsybouleva et al. (2004) observed that myocardial aldosterone and
aldosterone synthase (CYP11B2; 124080) mRNA levels were elevated by 4-
to 6-fold in patients with hypertrophic cardiomyopathy compared to
controls. In studies in rat cardiomyocytes, they found that aldosterone
increased expression of several hypertrophic markers via protein kinase
D (PRKCM; 605435) and increased collagens and TGFB1 (190180) via
PI3K-delta (PIK3CD; 602839). Inhibition of PRKCM and PIK3CD abrogated
the hypertrophic and profibrotic effects, respectively, as did the
mineralocorticoid receptor antagonist spironolactone. In a mouse model
of hypertrophic cardiomyopathy, spironolactone reversed interstitial
fibrosis, decreased myocyte disarray, and improved diastolic function.
Tsybouleva et al. (2004) concluded that aldosterone is a major link
between sarcomeric mutations and cardiac phenotype in CMH.

CLINICAL MANAGEMENT

Wilson et al. (1983) observed marked improvement in the manifestations
of familial hypertrophic cardiomyopathy when affected persons with
hyperthyroidism were treated for the latter condition. This prompted
them to suggest that antithyroid therapy 'should be considered in this
form of cardiomyopathy.'

In discussing the management of hypertrophic cardiomyopathy, Spirito et
al. (1997) reviewed heterogeneity of clinical and genetic features and
stated that 'the diverse clinical and genetic features of hypertrophic
cardiomyopathy make it impossible to define precise guidelines for
management.' The treatment of symptoms to improve quality of life and
the identification of patients who are at high risk for sudden death and
require aggressive therapy are 2 distinct issues that must be addressed
by largely independent strategies. The stratification of risk and the
prevention of sudden death were discussed.

Ventricular tachycardia or fibrillation is thought to be the principal
mechanism of sudden death in patients with hypertrophic cardiomyopathy.
Maron et al. (2000) conducted a retrospective study, the results of
which indicated that in high-risk patients with hypertrophic
cardiomyopathy, implantable defibrillators are highly effective in
terminating such arrhythmias, indicating that these devices have a role
in the prevention of sudden death. In comments on the study of Maron et
al. (2000), Watkins (2000) stated that for most patients with
hypertrophic cardiomyopathy, the risk is not high enough to offset the
adverse effects of an implantable defibrillator. He suggested the
creation of an international registry to document discharge rates after
implantation for each of the indicators of risk. Ideally, the data
should include molecular genetic information, since the underlying
mutation will itself be predictive. He cited the cohort studies of
McKenna et al. (1985) in which patients with hypertrophic cardiomyopathy
who were treated with low-dose amiodarone compared with untreated
historical controls suggested that long-term treatment was partially
protective; and the work of Ostman-Smith et al. (1999), indicating that
high doses of beta-blockers may also confer protection. Since there has
been an excess rate of sudden death during or shortly after exercise,
most physicians recommend that patients with hypertrophic cardiomyopathy
avoid competitive sports or intensive exertion.

In a study of 480 consecutive patients with hypertrophic cardiomyopathy,
Spirito et al. (2000) found that the magnitude of hypertrophy is
directly related to the risk of sudden death and then is a strong and
independent predictor of prognosis. Young patients with extreme
hypertrophy, even those with few or no symptoms, appeared to be at
substantial long-term risk and thus were considered for interventions to
prevent sudden death. Most patients with mild hypertrophy were at low
risk and were reassured regarding their prognosis.

Ho et al. (2002) studied confirmed MYH7 mutation heterozygotes using
echocardiography, including Doppler tissue imaging. Left ventricular
ejection fraction was significantly higher in mutation carriers than in
normal controls. Mean early diastolic myocardial velocities were
significantly lower in mutation carriers, irrespective of whether
hypertrophy was already present. Overall the authors concluded that
abnormalities of diastolic function were detectable before the onset of
myocardial hypertrophy in mutation carriers, providing a mechanism for
predicting affected individuals.

POPULATION GENETICS

In a discussion of hypertrophic cardiomyopathy, Maron et al. (1987)
stated that approximately 45% of cases are sporadic. New mutations
cannot be the explanation for all of the sporadic cases; hence, there
may be other etiologically distinct disorders represented in the group
of hypertrophic cardiomyopathies. Systematic echocardiographic surveys
of families of patients with hypertrophic cardiomyopathy have identified
relatives older than 50 years of age with mild and localized left
ventricular hypertrophy. Thus, the true proportion of sporadic cases may
not be as high as 45%.

*FIELD* SA
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(1998); Manchester (1963); Masuya et al. (1982); Powell et al. (1973);
Smith et al. (1976); Solomon et al. (1990); Taylor et al. (2003);
Wei et al. (1980); Wood et al. (1962)
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29. Goodwin, J. F.; Krikler, D. M.: Arrhythmia as a cause of sudden
death in hypertrophic cardiomyopathy. Lancet 308: 937-940, 1976.
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30. Greaves, S. C.; Roche, A. H. G.; Neutze, J. M.; Whitlock, R. M.
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31. Hardarson, T.; Curiel, R.; de la Calzada, C. S.; Goodwin, J. F.
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32. Haugland, H.; Ohm, O.-J.; Boman, H.; Thorsby, E.: Hypertrophic
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33. Hejtmancik, J. F.; Brink, P. A.; Towbin, J.; Hill, R.; Brink,
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37. Ho, C. Y.; Sweitzer, N. K.; McDonough, B.; Maron, B. J.; Casey,
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42. Jeschke, B.; Uhl, K.; Weist, B.; Schroder, D.; Meitinger, T.;
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56. Masuya, K.; Murakami, E.; Takekoshi, N.; Matsui, S.; Murakami,
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58. McKenna, W. J.: Personal Communication. London, England 5/30/1993.

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62. Motulsky, A. G.: The HLA complex and disease: some interpretations
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63. Nasser, W. K.; Williams, J. F.; Mishkin, M. E.; Childress, R.
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638-652, 1967.

64. Ostman-Smith, I.; Wettrell, G.; Riesenfeld, T. A.: A cohort study
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65. Pare, J. A. P.; Fraser, R. G.; Pirozynski, W. J.; Shanks, J. A.;
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66. Powell, W. J.; Whiting, R. B.; Dinsmore, R. E.; Sanders, C. A.
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67. Richard, P.; Charron, P.; Carrier, L.; Ledeuil, C.; Cheav, T.;
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109: 3258 only, 2004.

68. Richard, P.; Isnard, R.; Carrier, L.; Dubourg, O.; Donatien, Y.;
Mathieu, B.; Bonne, G.; Gary, F.; Charron, P.; Hagege, A.; Komajda,
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542-545, 1999.

69. Rosenzweig, A.; Watkins, H.; Hwang, D.-S.; Miri, M.; McKenna,
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of familial hypertrophic cardiomyopathy by genetic analysis of blood
lymphocytes. New Eng. J. Med. 325: 1753-1760, 1991.

70. Ross, R. S.; Knowlton, K. U.: Two brothers with unexplained cardiomegaly:
initial clues to the molecular basis of a hereditary cardiac disease. Trends
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71. Seidman, C.: Hypertrophic cardiomyopathy: from man to mouse. J.
Clin. Invest. 106: S9-S13, 2000.

72. Seidman, J. G.; Seidman, C.: The genetic basis for cardiomyopathy:
from mutation identification to mechanistic paradigms. Cell 104:
557-567, 2001.

73. Smith, E. R.; Heffernan, L. P.; Sangalang, V. E.; Vaughan, L.
M.; Flemington, C. S.: Voluntary muscle involvement in hypertrophic
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566-572, 1976.

74. Solomon, S. D.; Geisterfer-Lowrance, A. A. T.; Vosberg, H.-P.;
Hiller, G.; Jarcho, J. A.; Morton, C. C.; McBride, W. O.; Mitchell,
A. L.; Bale, A. E.; McKenna, W. J.; Seidman, J. G.; Seidman, C. E.
: A locus for familial hypertrophic cardiomyopathy is closely linked
to the cardiac myosin heavy chain genes, CRI-L436, and CRI-L329 on
chromosome 14 at q11-q12. Am. J. Hum. Genet. 47: 389-394, 1990.

75. Solomon, S. D.; Jarcho, J. A.; McKenna, W.; Geisterfer-Lowrance,
A.; Germain, R.; Salerni, R.; Seidman, J. G.; Seidman, C. E.: Familial
hypertrophic cardiomyopathy is a genetically heterogeneous disease. J.
Clin. Invest. 86: 993-999, 1990.

76. Spirito, P.; Bellone, P.; Harris, K. M.; Bernabo, P.; Bruzzi,
P.; Maron, B. J.: Magnitude of left ventricular hypertrophy and risk
of sudden death in hypertrophic cardiomyopathy. New Eng. J. Med. 342:
1778-1785, 2000.

77. Spirito, P.; Chiarella, F.; Carratino, L.; Berisso, M. Z.; Bellotti,
P.; Vecchio, C.: Clinical course and prognosis of hypertrophic cardiomyopathy
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78. Spirito, P.; Seidman, C. E.; McKenna, W. J.; Maron, B. J.: The
management of hypertrophic cardiomyopathy. New Eng. J. Med. 336:
775-782, 1997.

79. Tajsharghi, H.; Oldfors, A.; Macleod, D. P.; Swash, M.: Homozygous
mutation in MYH7 in myosin storage myopathy and cardiomyopathy. Neurology 68:
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80. Taylor, R. W.; Giordano, C.; Davidson, M. M.; d'Amati, G.; Bain,
H.; Hayes, C. M.; Leonard, H.; Barron, M. J.; Casali, C.; Santorelli,
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: A homoplasmic mitochondrial transfer ribonucleic acid mutation as
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83. Uro-Coste, E.; Arne-Bes, M.-C.; Pellissier, J.-F.; Richard, P.;
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84. Van Driest, S. L.; Vasile, V. C.; Ommen, S. R.; Will, M. L.; Tajik,
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85. Wagner, J. A.; Sax, F. L.; Weisman, H. F.; Porterfield, J.; McIntosh,
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Hyperthyroidism and familial hypertrophic cardiomyopathy. Arch. Intern.
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Gow, R.: Myocardial bridging in children with hypertrophic cardiomyopathy--a
risk factor for sudden death. New Eng. J. Med. 339: 1201-1209, 1998.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Asymmetric septal hypertrophy;
Apical hypertrophy (in some patients);
Subaortic stenosis;
Hypertrophic cardiomyopathy;
Presystolic gallop;
Palpitation;
Arrhythmia;
Congestive heart failure;
Sudden death

MUSCLE, SOFT TISSUE:
Myosin storage myopathy (in some patients)

MOLECULAR BASIS:
Caused by mutation in the myosin, heavy polypeptide-7, cardiac muscle,
beta gene (MYH7, 160760.0001)

*FIELD* CN
Marla J. F. O'Neill - revised: 06/26/2012

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 06/26/2012

*FIELD* CN
Ada Hamosh - updated: 01/08/2014
Marla J. F. O'Neill - updated: 9/4/2013
Marla J. F. O'Neill - updated: 4/6/2011
Marla J. F. O'Neill - updated: 3/25/2011
Marla J. F. O'Neill - updated: 6/7/2010
Marla J. F. O'Neill - updated: 5/11/2010
Marla J. F. O'Neill - updated: 6/24/2008
Marla J. F. O'Neill - updated: 6/4/2008
Marla J. F. O'Neill - updated: 12/4/2007
Marla J. F. O'Neill - updated: 1/18/2006
Carol A. Bocchini - updated: 8/12/2005
Marla J. F. O'Neill - updated: 7/8/2004
George E. Tiller - updated: 12/10/2003
Victor A. McKusick - updated: 11/18/2003
Victor A. McKusick - updated: 11/4/2003
Victor A. McKusick - updated: 5/9/2003
Victor A. McKusick - updated: 3/19/2003
Victor A. McKusick - updated: 11/7/2002
Victor A. McKusick - updated: 8/22/2002
Paul Brennan - updated: 8/7/2002
Michael J. Wright - updated: 7/26/2002
Michael J. Wright - updated: 6/28/2002
Victor A. McKusick - updated: 8/7/2000
Victor A. McKusick - updated: 7/14/2000
Paul Brennan - updated: 4/10/2000
Victor A. McKusick - updated: 2/15/2000
Victor A. McKusick - updated: 12/2/1998
Victor A. McKusick - updated: 5/9/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 01/08/2014
carol: 10/8/2013
mgross: 10/4/2013
carol: 9/4/2013
carol: 5/24/2013
carol: 2/14/2013
carol: 6/6/2012
terry: 4/26/2011
terry: 4/25/2011
carol: 4/22/2011
wwang: 4/8/2011
terry: 4/7/2011
terry: 4/6/2011
carol: 3/25/2011
terry: 3/25/2011
alopez: 1/14/2011
carol: 6/8/2010
carol: 6/7/2010
carol: 6/3/2010
wwang: 5/17/2010
wwang: 5/12/2010
terry: 5/11/2010
wwang: 2/16/2010
wwang: 2/15/2010
carol: 2/4/2010
wwang: 2/3/2010
wwang: 6/25/2009
terry: 6/3/2009
terry: 2/10/2009
carol: 9/8/2008
wwang: 7/14/2008
wwang: 6/24/2008
carol: 6/4/2008
terry: 6/4/2008
carol: 12/4/2007
terry: 12/4/2007
joanna: 2/24/2006
alopez: 2/16/2006
terry: 2/15/2006
wwang: 1/18/2006
carol: 8/12/2005
carol: 5/9/2005
joanna: 3/14/2005
carol: 7/8/2004
terry: 7/8/2004
carol: 6/16/2004
carol: 3/30/2004
mgross: 12/10/2003
alopez: 11/18/2003
terry: 11/11/2003
tkritzer: 11/10/2003
tkritzer: 11/6/2003
terry: 11/4/2003
carol: 5/9/2003
terry: 5/9/2003
terry: 3/19/2003
joanna: 3/4/2003
carol: 11/8/2002
terry: 11/7/2002
carol: 8/23/2002
terry: 8/22/2002
alopez: 8/7/2002
tkritzer: 8/2/2002
tkritzer: 8/1/2002
terry: 7/26/2002
alopez: 6/28/2002
terry: 6/28/2002
alopez: 3/12/2002
alopez: 3/11/2002
mcapotos: 8/28/2000
mcapotos: 8/11/2000
terry: 8/7/2000
carol: 7/14/2000
terry: 7/14/2000
alopez: 4/12/2000
alopez: 4/10/2000
alopez: 3/22/2000
mcapotos: 2/18/2000
terry: 2/15/2000
mgross: 12/6/1999
mgross: 11/24/1999
terry: 12/11/1998
carol: 12/8/1998
terry: 12/2/1998
terry: 11/11/1997
terry: 11/10/1997
mark: 7/9/1997
alopez: 6/27/1997
alopez: 6/3/1997
alopez: 5/9/1997
alopez: 5/7/1997
jamie: 2/26/1997
jamie: 2/18/1997
mark: 8/15/1996
mark: 4/29/1996
terry: 4/24/1996
John: 11/14/1995
mimadm: 6/7/1995
pfoster: 3/30/1995
davew: 8/16/1994
carol: 5/11/1994
warfield: 3/29/1994

MIM 606566
*RECORD*
*FIELD* NO
606566
*FIELD* TI
*606566 MYOSIN LIGHT CHAIN KINASE 2; MYLK2
;;MYOSIN LIGHT POLYPEPTIDE KINASE, SKELETAL/CARDIAC;;
read moreMLCK, SKELETAL/CARDIAC
*FIELD* TX

CLONING

In order to study the phosphorylation of the regulatory light chain of
myosin (RLC; 160781), Davis et al. (2001) cloned a myosin light chain
kinase, MYLK2, from human heart. The authors stated that MYLK2 is
identical to skeletal muscle MLCK. The 596-amino acid MYLK2 protein is
89% homologous to rabbit skeletal Mlck; most of the discordance between
the rabbit and human sequences is in the first 250 residues, before the
start of the catalytic region.

GENE STRUCTURE

Davis et al. (2001) determined that the MYLK2 gene contains 12 exons.

MAPPING

Davis et al. (2001) obtained a P1 genomic clone containing the MYLK2
gene that maps to chromosome 20q13.3.

GENE FUNCTION

In human, mouse, and rabbit cardiac tissue, Davis et al. (2001)
identified a spatial gradient from high (epicardial) to low
(endocardial) levels of phosphorylated myosin RLC that correlated with
levels of MYLK2. They suggested that this uneven distribution of MYLK2
might be the reason MYLK2 had not been detected in heart previously.
Mechanical studies of single slow muscle fibers showed that the spatial
gradient of RLC phosphorylation increased tension, decreased the stretch
activation response of epicardial fibers, and produced the converse
effect in endocardium.

MOLECULAR GENETICS

Davis et al. (2001) screened the MYLK2 genes from 490 unrelated patients
with cardiac hypertrophy and 189 normal controls for mutations. A
portion of the MYLK2 gene from 500 coronary artery disease patients was
also screened. A number of polymorphisms were observed, but only 1
pathogenic mutation was identified (see 606566.0001).

*FIELD* AV
.0001
CARDIOMYOPATHY, HYPERTROPHIC, MIDVENTRICULAR, DIGENIC
MYLK2, ALA87VAL

Davis et al. (2001) identified a double point mutation in the MYLK2 gene
on the maternal haplotype in a 13-year-old white male proband with early
midventricular hypertrophic cardiomyopathy (see 192600). The MYLK2
mutations were ala87 to val (A87V) and ala95 to glu (A95E; 606566.0002).
The proband also inherited a glu743-to-asp mutation (E743D; 160760.0024)
in the beta-myosin gene (160760) from his father. Although the son had
significant disease at an early age, the father and mother came to
medical attention only after the diagnosis of the son. Echocardiographic
evaluation showed that both parents had similarly abnormal
asymmetrically thickened hearts. Although the kindred was too small for
linkage analysis, kinetic studies revealed that the mutant MYLK2 had a
V(max) almost double that of wildtype MYLK2, which the authors suggested
may stimulate cardiac hypertrophy. Davis et al. (2001) concluded that
the increased severity of the disease at such a young age in the proband
suggests a compound effect.

.0002
CARDIOMYOPATHY, HYPERTROPHIC, MIDVENTRICULAR, DIGENIC
MYLK2, ALA95GLU

See 606566.0001 and Davis et al. (2001).

*FIELD* RF
1. Davis, J. S.; Hassanzadeh, S.; Winitsky, S.; Lin, H.; Satorius,
C.; Vemuri, R.; Aletras, A. H.; Wen, H.; Epstein, N. D.: The overall
pattern of cardiac contraction depends on a spatial gradient of myosin
regulatory light chain phosphorylation. Cell 107: 631-641, 2001.

*FIELD* CN
Marla J. F. O'Neill - updated: 6/23/2008

*FIELD* CD
Stylianos E. Antonarakis: 12/17/2001

*FIELD* ED
mgross: 06/23/2008
mgross: 6/23/2008
mgross: 12/18/2001
mgross: 12/17/2001