Sarcomeric protein mutations in dilated cardiomyopathy
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Sarcomeric Protein Mutations in Dilated Cardiomyopathy. DCM. A heart disease characterized by dilatation and impaired contraction of the left ventricle or both ventricles. A relatively common disease, affecting about 36.5 out of 100,000 people, of which, 25–30% are familial DCM.

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  • A heart disease characterized by dilatation and impaired contraction of the left ventricle or both ventricles.

  • A relatively common disease, affecting about 36.5 out of 100,000 people, of which, 25–30% are familial DCM.

  • Autosomal dominant familial DCM accounts for 56% of all familial DCMs, and the causes of this form of DCM is strongly associated with mutations in proteins of the cardiac myocyte.

Mutations associated with dcm
Mutations associated with DCM

  • Identified in the proteins of the sarcomere, cytoskeleton, and the sarcolemma.

  • In most diseased hearts, only single mutations are identified

  • All mutations lead to the same disease phenotype characteristic of DCM.

  • A progressive process starting from the initial effects of the mutations on contractility.

  • The convergence of protein dysfunction signals to a common pathway leading to the manifestation and progression of DCM

Mutated proteins
Mutated proteins

  • Mutations have been identified in β-myosin heavy chain (β-MHC), myosin binding protein-C (MyBP-C), actin, α- tropomyosin (Tm), troponin T (TnT), troponin I (TnI), troponin C (TnC), of the sarcomere; and titin, T-cap, desmin, vinculin, and muscle LIM protein (MLP) of the cytoskeleton.

Dcm associated mutations found in myh7
DCM Associated Mutations Found in MYH7

  • Of the total number of DCM associated mutations identified, the most prevalent are mutations in the MYH7 gene, which encodes for the β-myosin heavy chain (β-MHC) protein.

  • All of the myosin mutations were discovered through genetic screening studies of patients who have been diagnosed with idiopathic DCM.

Mutation types
Mutation types

  • β-myosin heavy chain mutations associated with DCM can be grouped into those which are found in the S1, those which are not found in the S1, and those which transition to DCM from HCM.

Cardiac myosin
Cardiac myosin

  • In cardiac muscle, two MHCs and two each of regulatory and essential light chains form the complete myosin molecule.

  • The structure of myosin is comprised of head, neck, and tail regions.

  • The myosin head, also known as myosin subfragment 1 (S1), functions as the catalytic portion of the myosin structure.

  • The essential and regulatory light chains wrap around the base of the head mediate myosin function.

Crystal structure of myosin s1
Crystal structure of myosin-S1

  • The relative positions of the DCM mutations are foundin the myosin head.

  • The seven mutations which are associated with DCM, and the three which are associated with DCM thattransitions from HCM, are shown.

Mutation sites
Mutation sites

  • Myosin mutations listed in Table 1, 10 in the S1 region of myosin, and 6 in the tail region.

  • The mutations which localize to the head motor domain could affect the actin-myosin interaction, thereby causing contractile dysfunction.

  • The mutations found in the tail region, occur in highly conserved residues, the substitution of which, may affect the structure of the myosin molecule.


  • Found in the highly conserved α-helical structure of the 50 kDa domain in myosin, which contributes to the tight binding of actin.

  • The proline for serine substitution introduces a kink in the α-helix structure, possibly disrupting stereospecific interactions between myosin and actin.


  • Found in the center of the region known as the converter region, which is responsible for the transmittal of movement from the myosin head to the neck.

Ala223thr and ser642leu
Ala223Thr and Ser642Leu

  • Ala223Thr mutation causes a charge change in a location near the ATP binding site of myosin.

  • Ser642Leu mutation is located in the actin-myosin interaction region.

  • The effects of these mutations are speculative, since functional studies of the mutations have yet to be reported.

Mutations at myosin tail
Mutations at myosin tail

  • Two mutations which are found in the myosin tail, Arg1053Gln and Arg1500Trp, are both weakly associated with DCM.

  • Arg1053Gln is associated with DCM which had transitioned from HCM, and the Arg1500Trp mutation has no evidence for familial heritage.

Cardiac myosin binding protein c
Cardiac Myosin Binding Protein C

  • cMyBP-C: a protein associated with the thick filament, localizes to the cross-bridge containing C zones of the sarcomere, through interactions with specific regions of titin and myosin.

  • Contains several phosphorylation sites, play a role in regulating force generation

  • Not essential for cardiac development and function, but involved in determining efficiency of muscle contraction.

Mutations sites for myosin and titin

  • cMyBP-C is second only to myosin, in the number of HCM associated mutations.

  • Mutations result in the expression of truncated forms of cMyBP-C.

  • Only three mutations in cMyBP-C associated with DCM, Asn948Thr, Arg820Gln, and a nonsense mutation Gln1012X.

Dcm associated mutations found in actin
DCM associated mutations found in actin sites for myosin and titin

  • Glu361Gly and Arg312His.

  • Any alteration to its amino acid sequence may have profound effects on the structure and its interaction with myosin, Tm, and possibly even itself (actin polymerization).

Dcm associated mutations in tropomyosin
DCM Associated Mutations in Tropomyosin mutations.

  • Through Ca2+ dependent movement transmitted via the Tn complex, Tm sterically blocks or opens the myosin binding sites on actin. This regulatory mechanism is essential for muscle contraction and relaxation.

  • Only three known DCM associated mutations in Tm, Glu40Lys, Glu54Lys, and Glu180Val.

Tn complex tnt tni and tnc
Tn complex: thin filament.TnT, TnI, and TnC.

  • TnT has important structural and regulatory roles in the thin filament, as the arm holding the Tn complex to Tm. Through its N-terminal end, TnT strongly binds to Tm, while the C-terminal end interacts with TnI and TnC.

  • TnI is the inhibitor of actin and myosin interaction. The binding of actin in low Ca2+ and the alternative binding of TnC in the presence of high Ca2+, by the inhibitory region of TnI, provides a Ca2+ sensitive mechanism for inhibition of muscle

  • TnC is the main Ca2+ buffer in the sarcomere.

Calcium switch
Calcium switch thin filament.

  • As intracellular Ca2+ concentration increases, the binding of Ca2+ to the regulatory site of TnC causes a conformational change in TnC and TnI.

  • TnC’s affinity for TnI increases, while TnI’s affinity for actin decreases.

  • The decrease in TnI interaction with actin, caused by Ca2+ binding to TnC, and the subsequent conformational changes in the Tn subunits, allow movement of Tm along the actin filament.

  • The movement of Tm facilitates the interaction between myosin and actin, leading to muscle contraction.

Tnt activates muscle contraction
TnT activates muscle contraction thin filament.

  • In the presence of TnI and TnC, there is a Ca2+ dependent activation of actomyosin ATPase rates, which results from the direct interaction of TnT with TnC.

  • The direct interaction of TnT with TnC in mediating activation, suggests a dual role for Ca2+ binding to TnC, the release of the ATPase inhibition by TnI, and the activation of the ATPase through interaction with TnT

Dcm associated mutations in tn
DCM Associated Mutations in Tn thin filament.

  • DCM related mutations have been found in all three subunits of Tn.

  • All display functional characteristics distinct from those caused by HCM associated mutations.

  • In contrast to the mutations associated with familial HCM, the DCM associated mutations are all presented with slightly decreased Ca2+ sensitivities and decreased actomyosin ATPase rates.

Tnt mutations i
TnT mutations I thin filament.

  • Two mutations, Arg92Trp and Lys273Glu, start off as HCM.

  • The arginine to tryptophan mutation in position 92, occurs in the Tm binding region of TnT.

  • The lysine to glutamic acid mutation in position 273, associated with the transition from HCM, results in a charge change in an important binding site for TnI or TnC.

Tnt mutations ii
TnT mutations II thin filament.

  • Six mutations occur in the C-terminal half of TnT, where it interacts with TnI and TnC, Arg131Trp, Arg141Trp, Ala171Ser, Arg205Leu, Lys210del, and Asp270Asn.

Tni mutation
TnI mutation thin filament.

  • The mutation in TnI, Ala2Val, found in the TNNI3 gene, is associated with recessive DCM.

  • Significant impairment of TnI and TnT interaction when compared with wild-type control.

Tnc mutations
TnC mutations thin filament.

  • The TnC mutation associated with DCM, Gly159Gln, is localized in a domain constitutively occupied by Ca2+ .

  • A mammalian 2-hybrid assay demonstrated an impaired interaction between TnT and TnC when compared with wild-type.

Titin thin filament.

  • Known as connectin

  • A giant muscle protein expressed in cardiac and skeletal muscles.

  • Referred to as the third myofilament of the cardiac muscle sarcomere

  • Spans the entire half of the sarcomere from Z-line to M-line, and two titins form a continuous myofilament along the whole length of the sarcomere by overlapping at the M-line.

Dcm associated mutations in non contractile proteins
DCM Associated Mutations in Non-Contractile Proteins sarcomere

  • MLP is a member of the cysteine-rich protein family, whose function is implicated in muscle differentiation and sarcomere assembly, through its interactions with zyxin and α-actinin.

  • Mice with deficiencies in MLP are reported to exhibit chamber dilation and contractile dysfunction, characteristic of DCM

  • W4R in MLP causes defects in its interaction with telethonin cap(T-cap)

  • Gln9Arg and Lys69Arg affect its interaction withα-actinin-2.

Dcm associated mutations in t cap
DCM Associated Mutations in T-cap sarcomere

  • T-cap is a 19 kD protein, whose role as a titin binding protein at the Z-disc is required for normal sarcomere development

  • The interaction betweenT-cap and titin requires the presence of MLP.

  • T-cap R87Q, E132Q mutations cause an impairment of the MLP binding affinity.

Dcm associated mutations in desmin
DCM Associated Mutations in Desmin sarcomere

  • Desmin is a cytoskeletal protein which forms muscle specific intermediate filaments, connecting the nuclear and plasma membranes of cardiomyocytes.

  • Desmin is involved in the regulation of intermediate filament organization and structure during the cell cycle, through the post-translational modifications ofphosphorylation and glycosylation, in its tail domain.

  • It is found at the Z-lines and intercalated disks, and because of the connections it forms between the nuclear and plasma membranes, is believed to also play a role the stabilization of the sarcomere.

  • Ile451Met mutation identified sits in the carboxyl end of human desmin

Dcm associated mutations in metavinculin
DCM associated mutations in metavinculin sarcomere

  • Vinculin isoform larger than by 68 amino acids

  • Expressed only in cardiac and smooth muscle

  • In cardiac myocytes, localizes to intercalated disks and costameres with vinculin.

  • The head portion interacts with membrane-associated ligand proteins, while the other end interacts with actin filaments.

  • Have a unique role of anchoring actin filaments to intercalated discs in the heart.

  • Three mutations linked to DCM, Ala934Val, Arg975Trp, and

  • a Leu954del.