MYH6

Non syndromic associated CHDs overview

Complete transposition of great arteries (IVS) (1, 5.9%)

Patent foramen ovale (PFO) (1, 5.9%)

Aortic valvar stenosis - congenital (1, 5.9%)

Tricuspid atresia (2, 11.8%)

ASD within oval fossa (secundum) (12, 70.6%)

[edit] Synopsis

Cardiac muscle myosin, along with actin, is one of the major components the contractile system of cardiac muscle (sarcomere). Myosin is a hexamer consisting of two heavy chain subunits (alpha and beta), two light chain subunits and two regulatory subunits. The beta myosin heavy chain subunit (βMHC), adenosine triphosphatase (ATPase), is encoded by the MYH7 gene. This MHC isoform is predominantly expressed in the embryonic human heart. MYH6 encodes the alpha myosin heavy chain subunit (αMHC), a fast ATPase, and is up-regulated postnatally (Weiss A et al., 1996). Thyroid hormone (T3) signaling stimulates αMHC and inhibits βMHC transcription after birth. Hypothyroidism and cardiac stress induces an upregulation of βMHC and a downregulation of αMHC (Krenz M et al., 2004, Hang CT et al., 2010). This shift in the MHC composition of the cardiac muscle can influence cardiac function (Miyata S et al., 2000). A cardiac-specific microRNA (miR-208) encoded by an intron of the MYH6 gene, is required for cardiomyocyte hypertrophy, fibrosis, and expression of βMHC in response to stress and hypothyroidism (Van Rooij E et al, 2007).

[edit] Mutation studies

Mutations in MYH6 cause hyperthrophic cardiomyopathies (Carniel E et al., 2005) and sporadically also heart defects (Granados-Riveron JT et al., 2010).

[edit] Association studies

Holm H et al., 2011 performed a genome-wide SNP analysis in 792 Icelandic individuals with sick sinus syndrome (SSS) and 37,592 Icelandic population controls. A missense variant (c.2161C>T) in the MYH6 gene, with an allelic frequency of 0.38% in Icelanders, was found to be associated with sick sinus syndrome (Odds ratio = 12.53 and P = 1.5 × 10(-29)). The lifetime risk of being diagnosed with sick sinus syndrome was shown to be around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.

External references for MYH6

• ensembl: ENSG00000197616
• OMIM: 160710
• Search miRBase for MYH6
• Expression patterns from 4DXPress: MYH6
• MGI: MGI:97255
• ZFIN: ZDB-GENE-031112-1
• Wikipedia: MYH6
• Search Wikiproteins: MYH6
• Search Genetic Association Database: MYH6
• Search GeneTests: MYH6
• CHeartED:

Known phenotypes for MYH6

Non-syndromic

ASD within oval fossa (secundum)

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:15735645 (basic research ) PMID:20656787 (population study with screening of similar CHD patients and normal controls ) Inheritence: Nonsyndromic ASD; DCM or HCM (dilated or hypertrofic cardiomyopathy) Incidence: 1 family (and morpholino knock-down of expression of the chick MYH6 homolog eliminates the formation of ASD without overtly affecting atrial chamber formation) (PMID:15735645) Comments: Studies: (2) [ show ] [ hide ] Reference: PMID:15735645 Incidence: 8/8 patients Comments: Ching et al. detected a mutation in the MYH6 gene in a large family with atrial septal defects. Atrial septal defects were present in 8 individuals carrying the mutation. Reference: PMID:20656787 Incidence: 4/55 patients Comments: Granados-Riveron JT et al., 2010 performed mutation analysis of coding regions of the MYH6 gene in a cohort of 470 CHD patients. They have identified a stopcodon mutation, a splice acceptor site mutation as well as seven missense mutations. The splice site mutation and three missense mutations were found in four out of 55 probands with atrial septal defects. Add another study.

Aortic valvar stenosis - congenital

Support: unconfirmed: a single case report References: PMID:20656787 (population study with screening of similar CHD patients and normal controls ) Inheritence: Non-syndromic aortic valvar stenosis: autosomal dominant with variable expression and reduced penetrance. Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:20656787 Incidence: 1/18 patients Comments: Granados-Riveron JT et al., 2010 performed mutation analysis of coding regions of the MYH6 gene in a cohort of 470 CHD patients. They have identified a stopcodon mutation, a splice acceptor site mutation as well as seven missense mutations. One missense mutation was found in 1 out of 18 probands with aortic valvar stenosis. Add another study.

Complete transposition of great arteries (IVS)

Support: unconfirmed: a single case report References: PMID:20656787 (population study with screening of similar CHD patients and normal controls ) Inheritence: Non-syndromic transposition of the great arteries with variable expression and reduced penetrance. Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:20656787 Incidence: 1/50 patients Comments: Granados-Riveron JT et al., 2010 performed mutation analysis of coding regions of the MYH6 gene in a cohort of 470 CHD patients. They have identified a stopcodon mutation, a splice acceptor site mutation as well as seven missense mutations. One missense mutation was found in 1 out of 50 probands with transposition of the great arteries was present. Add another study.

Patent foramen ovale (PFO)

Support: unconfirmed: a single case report References: PMID:20656787 (population study with screening of similar CHD patients and normal controls ) Inheritence: Non-syndromic patent foramen ovale: autosomal dominant with reduced penetrance and variable expression. Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:20656787 Incidence: 1/1 patients Comments: Granados-Riveron JT et al., 2010 performed mutation analysis of coding regions of the MYH6 gene in a cohort of 470 CHD patients. They have identified a stopcodon mutation, a splice acceptor site mutation as well as seven missense mutations. One missense mutation was found in one individual with patent foramen ovale. Add another study.

Tricuspid atresia

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:20656787 (population study with screening of similar CHD patients and normal controls ) Inheritence: Autosomal dominant non-syndromic tricupid atresia with reduced penetrance and variable expression. Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:20656787 Incidence: 2/10 patients Comments: Granados-Riveron JT et al., 2010 performed mutation analysis of coding regions of the MYH6 gene in a cohort of 470 CHD patients. They have identified a stopcodon mutation, a splice acceptor site mutation as well as seven missense mutations. Tricupid atresia was present in one individual carrying the stop codon mutation and in individual carrying a missense mutation. Add another study.

Add another phenotype.

Syndromic

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Protein interaction partners

Patients reports for MYH6

Translocations

Add another translocation.

Mutations in MYH6

Mutation (DNA)	Mutation (peptide)	CHD	Reference	Other features	Inheritence	Additional info.
NM_002471.2_c.IVS37-2A.G		ASD within oval fossa (secundum)	PMID:20656787	Truncus arteriosus type 1.	Dominant Familial	show hide Genetic evidence The mutation was inherited from the unaffected mother. A female sibling of the patient died aged 9 weeks with truncus arteriosus. No sample was available for analysis. This variant was not found in 480 ethnically matched normal controls. in silico prediction The A.G transition in the splice acceptor site of intron 37 is likely to induce skipping of exon 38 which encodes a segment of the assembly-competent domain. Functional studies No functional studies were performed for this variant. Comments Further functional studies are required to show the effect of this variant on cardiac development.
NM_002471.2_c.3413C>A	NP_002462.2_p.1116R>S	ASD within oval fossa (secundum)	PMID:20656787	ASD	Dominant Sporadic	show hide Genetic evidence No samples were available from other members of the family. This variant was not found in 480 ethnically matched control subjects. in silico prediction The two myosin molecules of a dimer are bound by hydrophobic interactions between non-charged residues of the rod portion in positions ‘a’ and ‘d’ of the heptad unit, forming a helical band in the surface of each monomer, inducing the coiled-coil conformation of the complex. This band is in turn flanked by charged residues at the ‘e’ and ‘g’positions of the heptad unit that interact with residues of opposite charge in the other molecule of the dimer. The c.3413C>A substitution occurs at the ‘g’ heptad position of the second heptad unit of the 11th 28-residue repeat. A charged residue is required in this position to flank the hydrophobic helical surface involved in the interaction of both myosin molecules of the dimer. Functional studies No functional studies were performed for this variant. Comments Further functional studies are required to show the effect of this variant on cardiac development.
NM_002471.2_c.4164C>A	NP_002462.2_p.1366A>D	Aortic valvar stenosis - congenital	PMID:20656787	Non-syndromic aortic valvar stenosis	Dominant Familial	show hide Genetic evidence The variant was found in the father who has septal dyskinesia and minor subaortic ridge, in a male sibling with subaortic ridge and patent foramen ovale, in a second male sibling with patent foramen ovale and in an unaffected dyzygotic twin sister. This variant was not found in 480 normal controls. in silico prediction A negatively charged aspartic acid residue is introduced at position 1366, which is occupied in other sarcomeric myosins by non-charged amino acids. The mutation could reduce considerably the stability of the coiledcoil as it is located in the ‘d’ position in the heptad repeat, within the hydrophobic interaction surface, where a non-polar side chain is required. It has been shown that a single substitution in that position of the repeat can have a dramatic effect on the stability of the protein fold. Functional studies The A1336D variant significantly reduced the striated patterns with concomitant increase of non-striated pattern, suggesting that these two mutations dramatically increased myofibril disarray (Granados-Riveron JT et al., 2010). Comments
NM_002471.2_c.4395C>A	NP_002462.2_p.1443A>D	ASD within oval fossa (secundum)	PMID:20656787	ASD type secundum	Dominant Sporadic	show hide Genetic evidence No samples were available from other members of the family. This variant was not found in 480 ethnically matched control subjects. in silico prediction The two myosin molecules of a dimer are bound by hydrophobic interactions between non-charged residues of the rod portion in positions ‘a’ and ‘d’ of the heptad unit, forming a helical band in the surface of each monomer, inducing the coiled-coil conformation of the complex. This band is in turn flanked by charged residues at the ‘e’ and ‘g’positions of the heptad unit that interact with residues of opposite charge in the other molecule of the dimer. The c.4395C>A variant lies in the ‘c’ position of the fourth heptad unit of the 22nd 28-residue repeat. Functional studies No functional studies were performed for this variant. Comments Further functional studies are required to show the effect of this variant on cardiac development.
NM_002471.2_c.5661G>A	NP_002462.2_p.1865R>Q	ASD within oval fossa (secundum)	PMID:20656787	ASD type secundum	Dominant Sporadic	show hide Genetic evidence The mutation is also present in a male sibling who had a small ventricular septal defect that closed spontaneously, the mother with a dilated inferior vena cava and an apparently unaffected female sibling. This variant was not present in 480 normal controls. in silico prediction The two myosin molecules of a dimer are bound by hydrophobic interactions between non-charged residues of the rod portion in positions ‘a’ and ‘d’ of the heptad unit, forming a helical band in the surface of each monomer, inducing the coiled-coil conformation of the complex. This band is in turn flanked by charged residues at the ‘e’ and ‘g’positions of the heptad unit that interact with residues of opposite charge in the other molecule of the dimer. This mutation is found in the ‘c’ position of the fourth heptad unit of the 37th 28-residue repeat. Functional studies No functional studies were performed for this variant. Comments Further functional studies are required to show the effect of this variant on cardiac development.
NM_002471.2_c.755G>C	NP_002462.2_p.230A>P	Tricuspid atresia	PMID:20656787	Patient with tricuspid atresia, hypoplastic right ventricle, large secundum ASD and valvular and supravalvular pulmonary stenosis.	Dominant Familial	show hide Genetic evidence An unaffected sister and a father with left ventricle hypertrophy were found to be carrier. This variant was not found in 480 ethnically matched control subjects. in silico prediction The alanine residue found in the non-mutant protein is conserved in every muscle myosin sequence available and is predicted to disrupt the helical configuration of the segment contiguous to the Switch-1 loop N-terminus. Functional studies This c.755G>C variant significantly reduced the striated patterns with concomitant increase of non-striated pattern, suggesting that these two mutations dramatically increased myofibril disarray (Granados-Riveron JT et al., 2010). Comments
NM_002471.2_c.829C>G	NP_002462.2_p.252H>Q	Complete transposition of great arteries (IVS)	PMID:20656787	Transposition of the great arteries	Dominant Familial	show hide Genetic evidence The mother, with persistence of the foramen ovale, and the unaffected grandmother carry the mutation. This variant was not detected in 480 normal controls. in silico prediction The 252 residue is located within a conserved segment and is predicted to prevent the formation of a salt-bridge normally present between Strands 6 and 7 of the b-sheet forming part of the transducer region. Functional studies The H252Q variant shows significantly increased striated muscle and decreased non-striated type when compared with the non-mutant, suggesting a possible gain-of-function for this mutation (Granados-Riveron JT et al., 2010). Comments
NM_002471.2_c.1568G>T	NP_002462.2_p.503E>X	Tricuspid atresia	PMID:20656787	Patient with tricuspid atresia, restrictive ventricular septal defect and hypoplastic right ventricle.	Dominant Sporadic	show hide Genetic evidence This variant was inherited from an unaffected mother and grandmother. This variant was not found in 480 ethnically matched control subjects. in silico prediction This non-sense mutation is predicted to encode a truncated peptide of 500 residues containing most of the segments required for nucleotide and actin binding but lacking most of the lower 50 kDa domain and the entire 20 kDa domain as well as the neck and rod regions. Functional studies No functional studies were performed for this variant. Comments Further functional studies are required to show the effect of this variant on cardiac development.
NM_002471.2_c.2165G>A	NP_002462.2_p.700V>M	Patent foramen ovale (PFO)	PMID:20656787	Non-syndromic PFO	Dominant Sporadic	show hide Genetic evidence The mutation was absent in two clinically normal sons. This variant was not found in 480 ethnically matched control subjects. in silico prediction The mutation resulting in V700M is found within the N-terminal segment of the SH1 helix. The V700M mutant should impose a steric hindrance over the rotation and longitudinal translation of the SH1 helix at different stages of the contractile cycle. Functional studies Granados-Riveron JT et al., 2010 investigated the structural impact of MYH6 mutations on myofibrillar organization in murine myoblasts. The mutant protein GFP-MYH6V700M shows a pattern indistinguishable to that of non-mutant. Comments This variant was present in unaffected family members and was not shown to have a structural impact on myofibrillar organization.

Representation of protein MYH6

Heart expression domain of MYH6

No specified expression domain for MYH6

Add a new domain where gene MYH6 is expressed

Associated CHDs found by automated text mining

AGeneApart Method

• Atrial septum defect (05.04.01) (sig = 0.73)

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This page contributors

• Jeroen Breckpot - CME Leuven (Belgium) (association, mutation, study, Free text)