1. Medicine

Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes

  1. Lorenzo Alamo
  2. James S Ware
  3. Antonio Pinto
  4. Richard E Gillilan
  5. Jonathan G Seidman
  6. Christine E Seidman  Is a corresponding author
  7. Raúl Padrón  Is a corresponding author
  1. Instituto Venezolano de Investigaciones Científicas, Venezuela
  2. Imperial College London, United Kingdom
  3. Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, United Kingdom
  4. Harvard Medical School, United States
  5. Cornell High Energy Synchrotron Source, United States
  6. Brigham and Women’s Hospital and Howard Hughes Medical Institute, United States
https://doi.org/10.7554/eLife.24634
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Cite this article
  1. Lorenzo Alamo
  2. James S Ware
  3. Antonio Pinto
  4. Richard E Gillilan
  5. Jonathan G Seidman
  6. Christine E Seidman
  7. Raúl Padrón
(2017)
Effects of myosin variants on interacting-heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes
eLife 6:e24634.
https://doi.org/10.7554/eLife.24634
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4 figures, 7 videos, 5 tables and 7 additional files

Figures

Figure 1
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The molecular pathogenesis of hypertrophic (HCM) and dilated (DCM) cardiomyopathy assessed in the context of the myosin interacting-heads motif (IHM) paradigm.

Myosin interactions involved in IHM assembly and myosin motor domain (MD) functions that are altered by PVs and LPVs are depicted. (A) Relaxed healthy cardiac muscle contains myosin heads …

https://doi.org/10.7554/eLife.24634.002
Figure 2 with 2 supplements
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Structure of the human β-cardiac myosin interacting-heads motif.

(A) Quasi-atomic homologous model of human β-cardiac myosin interacting-heads motif (IHM) PDB 5TBY composed of blocked (BH) and free (FH) heads, fitted to the human cardiac thick filament 3D-map …

https://doi.org/10.7554/eLife.24634.003
Figure 2—figure supplement 1
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Calculated small angle X-ray solution scattering (SAXS) profile of PDB 5TBY (red line) matches experimental squid heavy meromyosin (HMM) SAXS profile (green dots) (Gillilan et al., 2013).

The comparison of model-based tarantula PDB 3JBH (blue dashed line) vs. human cardiac ventricular IHM PDB 5TBY (red line) scattering with measured squid HMM scattering profiles (green dots) in (A) …

https://doi.org/10.7554/eLife.24634.004
Figure 2—figure supplement 2
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Wide-eye stereo pairs that compare the PDB 5TBY model with crystal structures of fragments for human β-cardiac S1 MD fragment (PDB 4DB1) and S2.

(A) Superimposed MDs of S1 from the PDB 5TBY antavd a S1 fragment of human β-cardiac myosin S1 crystal structure PDB 4DB1 (AMPPNP rigor-like structure) See Video 2. Color code: PDB 5TBY: Blocked …

https://doi.org/10.7554/eLife.24634.005
Figure 3 with 9 supplements
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IHM PDB 5TBY models depicting pathogenic (PVs) and likely pathogenic variants (LPVs), in HCM and DCM (listed in Tables 1–3).

Each variant appears as a pair, one located on or associated with the blocked head (BH, olive) and one on the free head (FH, green). Associated proteins are the essential light chain (ELC …

https://doi.org/10.7554/eLife.24634.015
Figure 3—figure supplement 1
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Wide-eye stereo pairs of the IHM PDB 5TBY model showing HCM pathogenic variants (A) and DCM pathogenic and likely pathogenic variants (B).

(A) IHM PDB 5TBY model mapping 40 HCM pathogenic variants (that produced 39 distinct substitutions in MHC and four substitutions in the regulatory and essential light chains; Table 1, in the main …

https://doi.org/10.7554/eLife.24634.016
Figure 3—figure supplement 2
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Wide-eye stereo pair of the IHM PDB 5TBY model showing the five HCM variants that alter residues involved in IHM priming (intra-molecular interactions ‘g’ and ‘f’).

Three variants alter resides that participate in ‘f’ sub-interactions (‘f.1’: D906G, L908V; ‘f.2’: R663H) and two alter residues that participate in ‘g’ interactions (R453C and R870H). All chains …

https://doi.org/10.7554/eLife.24634.017
Figure 3—figure supplement 3
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Wide-eye stereo pair of the IHM PDB 5TBY model showing 13 HCM pathogenic variants involved in anchoring the IHM.

Intermolecular interactions between (‘j’, ‘i’) myosin and the essential light chain anchor the blocked head anchoring on the neighboring S2. Five substitutions are involved on interaction ‘j’ …

https://doi.org/10.7554/eLife.24634.018
Figure 3—figure supplement 4
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Wide-eye stereo pair of the IHM PDB 5TBY model showing sites of 25 HCM variants that alter IHM stabilizing residues.

Twenty-three MHC variants and two ELC variants alter IHM residues that dock the free head onto the blocked head (‘e’, ‘d’ and ‘a’ interactions). Nineteen MYH7 substitutions are at residues …

https://doi.org/10.7554/eLife.24634.019
Figure 3—figure supplement 5
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Wide-eye stereo pair of the IHM PDB 5TBY model showing four variants located in the RLC-RLC interface region.

Variants in MHC (S842N and F834L) and RLC (E22K and R58Q) alter residues that allow proper docking of the two opposite surfaces of the RLC-RLC interface when the IHM is initially assembled. The …

https://doi.org/10.7554/eLife.24634.020
Figure 3—figure supplement 6
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Sequence alignment of human cardiac, chicken skeletal and tarantula striated MHC with the locations of HCM variants.

Variant positions (arrowheads) are color-coded according their charge-change, as in Figure 3—figure supplement 1.

https://doi.org/10.7554/eLife.24634.021
Figure 3—figure supplement 7
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Sequence alignment of human cardiac, chicken skeletal and tarantula striated MHC with the locations of DCM variants.

Variant positions (arrowheads) are color-coded as in Figure 3—figure supplement 1.

https://doi.org/10.7554/eLife.24634.022
Figure 3—figure supplement 8
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Sequence alignment of human cardiac, chicken skeletal and tarantula striated ELC with the locations of HCM variants.

HCM variant positions are (arrowheads) color-coded as in Figure 3—figure supplement 1.

https://doi.org/10.7554/eLife.24634.023
Figure 3—figure supplement 9
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Sequence alignment of human cardiac, chicken skeletal and tarantula striated RLC with the location of HCM variants.

HCM variant positions are (arrowheads) color-coded as in Figure 3—figure supplement 1.

https://doi.org/10.7554/eLife.24634.024
Figure 4
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The location of 14 variants located on the mesa (Spudich, 2015; Homburger et al., 2016) of the blocked head (BH, olive) and free head (FH, green).

The three negatively-charged rings in the blocked head S2 are labeled R1, R2 and R3. The associated sarcomere proteins are depicted as in Figure 3. The myosin mesas are roughly orthogonal (blocked …

https://doi.org/10.7554/eLife.24634.027

Videos

Video 1
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A homologous human β-cardiac myosin IHM structure.

The PDB 5TBY IHM model is initially depicted as a ribbon structure that includes paired myosin heads (blocked head (BH), gold, free head (FH), olive), essential light chain (ELC associated with BH: …

https://doi.org/10.7554/eLife.24634.006
Video 2
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The motor domain (MD) of the PDB 5TBY model closely matches the crystal structure of a fragment for human β-cardiac S1 MD (PDB 4DB1).

The movie shows superimposed MDs of S1s from the PDB 5TBY model and a S1 fragment of PDB 4DB1 (S1 bound to adenylylimidodiphosphate (AMPPNP), a nonhydrolysable analogue of ATP to induce a rigor-like …

https://doi.org/10.7554/eLife.24634.007
Video 3
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The sub-fragment 2 (S2) of the PDB 5TBY IHM model closely matches the crystal structures of S2 for human β-cardiac (PDB 2FXM)(Blankenfeldt et al., 2006).

The movie shows the two S2 strands as ribbons of PDB 5TBY in gold and olive (blocked and free heads, respectively) and 2FXM in pink. See legend of Figure 2—figure supplement 2B.

https://doi.org/10.7554/eLife.24634.008
Video 4
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The PDB 5TBY IHM model shows that the blocked and free myosin heads are in the pre-powerstroke state (Zoghbi et al., 2004; Xu et al., 2003; Llinas et al., 2015) and bent at the ‘pliant region’ as defined by Houdusse et al. (2000).

The movie shows the free and blocked head structures of PDB 5TBY IHM model as ribbons in gold and olive respectively, versus the pre-powerstroke state PDB 1BR1 crystal structure (magenta). The ELC …

https://doi.org/10.7554/eLife.24634.009
Video 5
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Semi-transparent, space-filled PDB 5TBY IHM structure depicting the impact of HCM variants, when exposed to different IHM environments.

HCM variants reside on the myosin blocked head (gold), myosin free head (olive), essential light chain (associated with blocked head (brown) or free head, (purple)), and regulatory light chain …

https://doi.org/10.7554/eLife.24634.025
Video 6
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Semi-transparent, space-filled PDB 5TBY IHM structure depicting the impact of DCM variants when residing on the myosin blocked head (gold) and myosin free head (olive).

Variants are depicted as balls, colored according to the interactions that that disrupt: priming, green; anchoring, orange; stabilizing, pink, and scaffolding, white. Grey variants alter residues …

https://doi.org/10.7554/eLife.24634.026
Video 7
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Semi-transparent, space-filled 5TBY IHM structure depicting only HCM variants that reside on the blocked head and free head mesas.

The myosin blocked head (gold), myosin free head (olive), essential light chain (associated with blocked head (brown) or free head (purple)), and regulatory light chain (associated with blocked head …

https://doi.org/10.7554/eLife.24634.028

Tables

Table 1

HCM pathogenic variants (PVs) causing 39 MYH7, 2 MYL2, and 2 MYL3 amino acid substitutions.

https://doi.org/10.7554/eLife.24634.010
SubstitutionLocation*BH interaction*Type*FH interaction*Type*Δq†Motor Domain Function‡
MYH7Motor Domain
Y115HNear ATP Binding I+1
E170KNear ATP-binding IId.1Stabilizing+2
R249QNear ATP Binding III-2
I263TNear ATP Binding IV0
P307HNear ATP Binding IV+1
R403W/G/L/QCM-Loopd.1Stabilizing-2Actin interface 1
R442CNear ATP Binding Vd.1Stabilizing-2
R453CNear ATP Binding VgPrimingd.1Stabilizing-2
E483KNear RelayjAnchoringd.2Stabilizing+2
M515TRelayjAnchoringd.2Stabilizing0Relay
V606MHelix-loop-helixeStabilizing0Actin interface
R663HNear Loop 2f.2Priming-1
M690TSH2 helix0
I702NSH1 helix0
G708ASH1 helix0
G716RConverteriAnchoringd.2Stabilizing+2Converter
ELC-MHCScaffoldingConverter
R719W/QConverteri,Anchoringd.2Stabilizing-2Converter
ELC-MHCScaffoldingConverter
R723G/CConverteriAnchoringd.2Stabilizing-2Converter
ELC-MHCScaffoldingConverter
I736TConverterjAnchoringd.2Stabilizing0Converter
ELC-MHCScaffoldingConverter
G741W / RConverterjAnchoringd.2Stabilizing0 / + 2Converter
ELC-MHCScaffoldingConverter
K762RConverterjAnchoringd.2Stabilizing+1Converter
ELC-MHCScaffoldingConverter
K766QConverterd.2Stabilizing-1Converter
Regulatory Domain
A797TNeck-ELC interfaceELC-MHCScaffoldingELC-MHCScaffolding0
F834LHead-tail junctionRLC-MHCScaffoldingRLC-MHCScaffolding0
S2
S842NHead-tail junctionRLC-MHCScaffoldingRLC-MHCScaffolding0
R870HKinkgPriminggPriming-1
D906GRing1f.2Primingf.2Priming+1
L908VRing1f.2Primingf.2Priming0
L915PRing2aStabilizingaStabilizing0
E924KRing2aStabilizingaStabilizing+2
E930KRing2aStabilizingaStabilizing+2
Light Meromyosin
A1379TNear skip 2 residue0
R1781CNear skip 4 residue-2
MYL3Essential Light Chain
M149VChain FiAnchoringeStabilizing0
ELC-MHCScaffolding
H155DChain FiAnchoringELC-MHCScaffolding-2
ELC-MHCScaffoldingeStabilizing
MYL2Regulatory Light Chain
E22KNear S15RLC-RLCRegulatingRLC-RLCRegulating+2
RLC-MHCScaffoldingRLC-MHCScaffolding
R58QChains B-C loopRLC-RLCRegulating-2
RLC-MHCScaffoldingRLC-MHCScaffolding

  1. All PVs identified in 6112 HCM patients (Walsh et al., 2017) are shown. In MYH7 there are 40 PVs, leading to 39 distinct substitutions at 33 positions while in MYL2 and MYL3 there are four more pathogenic variants. HCM PVs located on the mesa are bolded.

  2. *Supplementary file 1 defines domain locations and Supplementary file 2 defines IHM interactions, refined using the PISA analysis (Krissinel and Henrick, 2007) that are highlighted as in Figure 3, excluding the two LMM substitutions. RLC–RLC denotes interface region between regulatory light chains.

  3. †Δq: variant induced electrical charge change. Δq defines whether the substituted amino acid changes the charge (bolded) or not (Δq = 0).

  4. ‡Motor domain functions are ascribed only to variants within involved residues. RLC–RLC denotes interface region between regulatory light chains. Variants at IHM interactions sites are colored according to the interaction affected: priming = green, anchoring = orange, stabilizing = pink, scaffolding = white, regulating = yellow.

Table 2

HCM likely pathogenic variants (LPVs) causing 95 MYH7 amino acid substitutions.

https://doi.org/10.7554/eLife.24634.011
SubstitutionLocation*BH interaction*Type*FH interaction*Type*Δq‡Motor Domain Function§
MYH7Motor Domain
R17CSH3hAnchoring-2
R143Q-2
K146N-1
R169G/K/SNear P-loopd.1Stabilizing−2/–1/−2
Q193RNear P-loop+2
A199VNear Loop 10
R204CLoop 1-2Actin interface
G214DLoop 1-1Actin interface
N232HNear Switch 2+1
D239NSwitch 1+1ATP-Binding III
R243H†Switch 1-1ATP-Binding III
F244CSwitch 10ATP-Binding III
K246INear Switch 1-1
F247LNear Switch 10
I248TNear Switch 10
G256ENear Switch 1-1
I263MNear ATP-Binding IV0
L267VNear ATP-Binding IV0
Y283C0
S291FNear I-loop0
D309NI-loop+1MD-RLC interface
I323NI-loop0MD-RLC interface
E328GNear I-loop+1
V338M0
K351ENear C-loop-2
G354SNear C-loop0
E374VC-Loopd.2Stabilizing+1Actin interface
A381DC-Loopd.2Stabilizing-1Actin interface
Y386CNear C-loopeStabilizing0
V406MCM-loopd.1Stabilizing0Actin Interface I
Y410DCM-loopd.1Stabilizing-1Actin Interface I
V411ICM-loopd.1Stabilizing0Actin Interface I
L427M0
T449SNear Switch 2gPrimingd.1Stabilizing0
R453S/HNear Switch 2gPrimingd.1Stabilizing0/–1
I457TNear Switch 20
I478NNear Switch 20
N479SNear Switch 20
M493V/L/IRelayjAnchoringd.2Stabilizing0Relay
E497G/DRelayjAnchoringd.2Stabilizing+1/0Relay
1521TNear Relay0
E536DH-loopf.2Priming0Actin Interface II
H576RLoop 3+1Actin Interface III
G584RNear Loop 3+2
V586ANear Loop 30
R652GNear Loop 2f.2Priming-2
K657QNear Loop 2f.2Priming-1
R663CNear Loop 2f.2Priming-2
R671CNear SH2 helix-2
R694C/HSH2 helix−2/–1
P710H/LConverter+1/0Converter
P731AConverterjAnchoring0Converter
ELC-MHCScaffolding
G733EConverterjAnchoringd.2Stabilizing-1Converter
ELC-MHCScaffolding
R739SConverterjAnchoringd.2Stabilizing-2Converter
ELC-MHCScaffolding
K740NConverterjAnchoringd.2Stabilizing-1Converter
ELC-MHCScaffolding
L749QConverterjAnchoring0Converter
ELC-MHCScaffolding
F758CConverterjAnchoring0Converter
ELC-MHCScaffolding
V763MConverterd.2Stabilizing0Converter
G768RConverter+2Converter
L781PPliantELC-MHCScaffoldingELC-MHCScaffolding0Pivot
R783HPliantELC-MHCScaffoldingELC-MHCScaffolding-1Pivot
Regulatory Domain
R787CNeck-ELC interfaceELC-MHCScaffoldingELC-MHCScaffolding-2
A797PNeck-ELC interfaceELC-MHCScaffoldingELC-MHCScaffolding0
L811PNeck-ELC-RLC interfaceELC-MHC
RLC-MHC		ScaffoldingRLC-MHCScaffolding0
S2
K847EHead-tail junction-2
E848GHead-tail junction+1
M849THead-tail junction
A850DHead-tail junction-1
R858HgPriminggPriming-1
E894GRing 1f.1Primingf.2Priming+1
L898VRing 1f.1Primingf.2Priming0
A901PRing 1f.1Primingf.2Priming0
E903GRing 1f.1Primingf.2Priming+1
Q914H+1
D928NRing 2aStabilizingaStabilizing+1
E929KRing 2aStabilizingaStabilizing+2
E930QRing 2aStabilizingaStabilizing+1
E949KRing 3+2
E967K+2
R1053Q-2
Light Meromyosin
E1356K+2
R1382QNear skip 2 residue-2
L1428S0
R1606CNear skip 3 residue-2
A1763T0
R1781HNear skip 4 residue-1
M1782VNear skip 4 residue

  1. All LPVs identified in 6112 HCM patients (Walsh et al., 2017) are shown. In MYH7 there 95 LPVs, leading to 95 distinct amino acid substitutions at 87 positions.

  2. *Supplementary file 1 defines domain locations and Supplementary file 2 defines IHM interactions, refined using the PISA analysis (Krissinel and Henrick, 2007) that are highlighted as in Figure 3, excluding the LMM variants. HCM LPVs located on the mesa are bolded.

  3. †R243H was identified in both HCM and DCM cohorts. RLC–RLC denotes interface region between regulatory light chains.

  4. ‡Δq: variant induced electrical charge change. Δq defines whether the substituted amino acid changes the charge (bolded) or not (Δq = 0).

  5. §Motor domain functions are ascribed only to variants within involved residues. Variants at IHM interactions sites are colored according to the interaction affected: priming = green, anchoring = orange, stabilizing = pink, scaffolding = white.

Table 3

DCM pathogenic variants (PVs) and likely pathogenic variants (LPVs) causing 27 MYH7 amino acid substitutions.

https://doi.org/10.7554/eLife.24634.012
SubstitutionLocation‡BH interaction‡Type‡FH interaction‡Type‡Δq§Motor Domain Function
MYH7Motor Domain
G144VNear ATP Binding I0
G178RATP-binding II (P-loop)+2ATP Binding II
G181RATP-binding II (P-loop)+2ATP Binding II
I201TNear 25/50 junction (Loop 1)0
R243H†ATP-binding III (Switch 1)-1ATP Binding III
G245EATP-binding III (Switch 1)-1ATP Binding III
I248FNear ATP-binding III0
R369QC-Loop (Loop 4)d.2Stabilizing-2Actin interface
D469YATP-binding V (Switch 2)+1ATP Binding V
I524VNear H-Loopf.2Priming0
E525KNear H-Loopf.2Priming+2
I533VH-Loopf.2Priming0Actin interface II
R567HActin-interface III (Loop 3)-1Actin interface III
N597KHelix-loop-helix+1Actin interface
C672FNear SH2 Helix0
R783PPliantELC-MHCScaffoldingELC-MHCScaffolding-2Pivot
S2
R904C*/HRing1f.2Primingf.2Priming−2/–1
E1152V+1
Light Meromyosin
R1193HNear skip 1 residue-1
E1286K+2
R1434C-2
D1450N+1
R1574W-2
Q1794E-1
E1801KNear skip 4 residue+2
E1914K+2.

  1. All PVs and LPVs identified in 1315 DCM patients (Walsh et al., 2017) are shown. In MYH7 there are 27 DCM pathogenic and likely pathogenic variants, leading to 27 distinct substitutions at 26 residues. DCM LPVs located on the mesa are bolded.

  2. *R904C is the only DCM PV.

  3. †R243H was identified in both HCM and DCM cohorts. In this cohort, no variants in MYL2 or MYL3 caused DCM.

  4. ‡Supplementary file 1 defines domain locations and Supplementary file 2 defines IHM interactions, refined using the PISA analysis (Krissinel and Henrick, 2007) that are highlighted as in Figure 3, excluding the LMM variants.

  5. §Δq: variant induced electrical charge change. Δq defines whether the substituted amino acid changes the charge (bolded) or not (Δq = 0).

  6. Motor domain functions are ascribed only to variants within involved residues. Variants at IHM interactions sites are colored according to the interaction affected: priming = green, stabilizing = pink, scaffolding = white.

Table 4

The distribution of HCM variants across IHM and MD functional residues.

https://doi.org/10.7554/eLife.24634.013
Specified siteVariants within siteRateAmino acids within siteExpected rateRate ratioP-value
IHM Interactions (All)730.5414470.23102.347.95e-15
Priming170.1261130.05842.162.64e-03
Anchoring240.1781560.08062.212.11e-04
Stabilizing480.3561890.09773.645.37e-16
Scaffolding240.1781200.06202.872.97e-06
MD Functional390.2891940.10002.897.87e-10

  1. The numbers of distinct pathogenic and likely pathogenic HCM variants (n = 135) affecting IHM interaction sites and motor domain (MD) functional residues are shown. Variant numbers are also tabulated separately for the four major IHM interactions: priming, anchoring, stabilizing and scaffolding. Note that a single variant may impact more than one interaction. The number of myosin amino acid residues (total protein length = 1935 residues) that compromise the IHM interaction sites or MD functions was used to determine the proportion of variants that would be expected to lie in the region of interest under the null (a uniform distribution), and the rates are compared with a binomial test. Full details of all variants are shown in Tables 1 and 2.

Table 5

The distribution of DCM variants across IHM and MD functional residues.

https://doi.org/10.7554/eLife.24634.014
Specified siteVariants within siteRateAmino acids within siteExpected rateRate ratioP-value
IHM Interactions (All)70.2594470.23101.1200.6550
Priming50.1851130.05843.1700.0186
Anchoring00.0001560.08060.0000.1650
Stabilizing10.0371890.09770.3790.5120
Scaffolding10.0371200.06200.5971.0000
MD Functional70.2592100.10902.3800.0222

  1. The numbers of distinct pathogenic and likely pathogenic DCM variants (n = 27) affecting IHM interactions and motor domain (MD) functional residues are shown. Variant numbers are also tabulated separately for the four major IHM interactions: priming, anchoring, stabilizing and scaffolding. Note that a single variant may impact more than one interaction. The number of myosin amino acid residues (total protein length = 1935 residues) that compromise the IHM interaction sites or MD functions was used to determine the proportion of variants that would be expected to lie in the region of interest under the null (a uniform distribution), and the rates are compared with a binomial test. Full details of all variants are shown in Table 3.

Additional files

Supplementary file 1

Domains of human β-cardiac myosin.

https://doi.org/10.7554/eLife.24634.029
Supplementary file 2

Intra- and inter-molecular interactions sequences involved in human β-cardiac myosin interacting-heads motif (IHM) PDB 5TBY.

https://doi.org/10.7554/eLife.24634.030
Supplementary file 3

HCM variants cluster on residues involved in IHM-related inter- and intra-molecular interactions.

https://doi.org/10.7554/eLife.24634.031
Supplementary file 4

DCM-causing variants cluster in distinct regions of MYH7 from HCM-causing variants.

https://doi.org/10.7554/eLife.24634.032
Supplementary file 5

Variants Clustered on the Myosin Mesa.

https://doi.org/10.7554/eLife.24634.033
Supplementary file 6

Comparison of prevalence of rare (ExAC global AF <1×10−4) missense variants in MYH7 in 6112 HCM cases and ExAC controls.

https://doi.org/10.7554/eLife.24634.034
Supplementary file 7

Leveraging regional distribution for the clinical interpretation of DCM-causing variants.

https://doi.org/10.7554/eLife.24634.035

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