BioMed Research International

Review Article

The Sarcomeric M-Region: A Molecular Command Center for Diverse Cellular Processes

Table 2

Disease-causing mutations in genes encoding structural proteins of the M-region.
ProteinMutationRegion on proteinEffectDiseaseReference
FHL-1K45SfsX1LIM domain 1UnknownHCM[177]
FHL-1R95WLinker region between LIM domain 1 and 2UnknownRBM[178]
FHL-1C101FLIM domain 2UnknownRBM[179]
FHL-1102–104 del KFCLIM domain 2UnknownRBM[179]
FHL-1C104R/YLIM domain 2UnknownRBM[179, 180]
FHL-1111–229 del ins GLIM domain 2UnknownEDMD[181]
FHL-1N112FfsX51LIM domain 2UnknownEDMD[181]
FHL-1W122S/CLIM domain 2UnknownSPM[182, 183]
FHL-1H123Y/Q/L/RLIM domain 2UnknownRBM[178, 184–186]
FHL-1K124RfsX6LIM domain 2UnknownEDMD[181]
FHL-1F127 ins 128ILIM domain 2UnknownXMPMA[187]
FHL-1C132FLIM domain 2UnknownRBM[186]
FHL-1C150Y/R/SLIM domain 2UnknownRBM[179, 185, 188]
FHL-1151–153 del VTCLIM domain 2UnknownRSS[179]
FHL-1C153Y/R/S/WLIM domain 2UnknownRBM[186]
FHL-1153StopLIM domain 2UnknownHCM[177]
FHL-1Delete exon 6 ins 84 bpLIM domain 3Loss of full length FHL-1A, increase in FHL-1CEDMD[189]
FHL-1K157VfsX36LIM domain 3UnknownEDMD[181]
FHL-1A168GfsX195LIM domain 3UnknownXMPMA[187]
FHL-1194StopLIM domain 3Premature stop codon and truncated protein corresponding to FHL-1CXMPMA[190]
FHL-1198StopLIM domain 3UnknownHCM[191]
FHL-1F200fs32XLIM domain 3UnknownHCM[192]
FHL-1C209RLIM domain 3UnknownEDMD/HCM[181, 193]
FHL-1C224WLIM domain 4UnknownXMPMA[187]
FHL-1H246YLIM domain 4UnknownXMPMA[190]
FHL-1C273LfsX11LIM domain 4UnknownEDMD[181]
FHL-1C276YLIM domain 4UnknownEDMD[181]
FHL-1 C276SLIM domain 4UnknownHCM[177]
FHL-1V280MNLS of FHL-1BUnknownXMPMA[190]
FHL-1E281StopExtreme COOH-terminusUnknownEDMD[181]
FHL-2G48SLIM domain 1Loss of titin bindingDCM[194]
sMyBP-CW236RM-motifLoss of actin and myosin bindingDA-1[195]
sMyBP-CR318StopIgC2Premature stop codon and truncated proteinLCCS4[196]
sMyBP-CY856HIgC8Loss of myosin bindingDA-1[195]
MyH 3841-841 del LLMMReduced catalytic activityDA Sheldon-Hall syndrome[197]
MyH 6A1004S
E1457K		LMMUnknownDCM[198]
MyH 6Q1065HLMMUnknownHCM[198]
MyH 6R1116S
A1366D
A1443D
R1865Q		LMMUnknownCHD[199]
MyH 7847-847 del KLMMUnknownHCM[200]
MyH 7M852TLMMUnknownHCM[201]
MyH 7R858CLMMUnknownHCM[200]
MyH 7R869GLMMUnknownHCM[201]
MyH 7R870HLMMUnknownHCM[202]
MyH 7883-883 del ELMMUnknownHCM[201]
MyH 7E894GLMMUnknownHCM[200]
MyH 7D906GLMMUnknownHCM[203]
MyH 7L908VLMMUnknownHCM with CCD[204]
MyH 7E921KLMMUnknownHCM[200]
MyH 7E924K
E949K		LMMUnknownHCM[205]
MyH 7D928VLMMUnknownHCM[206]
MyH 7E931KLMMUnknownHCM[200]
MyH 7E935KLMMUnknownHCM[207]
MyH 7D953HLMMUnknownHCM[200]
MyH 7T1019NLMMUnknownDCM[208]
MyH 7R1053QLMMUnknownHCM[209]
MyH 7G1057SLMMUnknownHCM[200]
MyH 7L1135R
LMMUnknownHCM[201]
MyH 7R1193SLMMUnknownDCM[208]
MyH 7E1218QLMMUnknownHCM[201]
MyH 7N1327KLMMReduced α-helical content of the rod domainHCM[210]
MyH 7E1356KLMMReduced α-helical content of the rod domainHCM[211]
MyH 7E1377M
A1379T
R1382W		LMMUnknownHCM[201]
MyH 7R1420WLMMUnknownHCM[200]
MyH 7E1426KLMMUnknownDCM[208]
MyH 7A1439PLMMUnknownMPD1[212]
MyH 7K1459NLMMUnknownHCM[200]
MyH 7L1467VLMMUnknownCongenital myopathy[213]
MyH 7L1481PLMMUnknownMPD1[214]
MyH 7R1500WLMMReduced α-helical content of the rod domainDCM[215]
MyH 7R1500P
1617-1617 del K		LMMUnknownLaing distal myopathy[216]
MyH 71508-1508 del ELMMUnknownMPD1[217]
MyH 7T1513SLMMUnknownHCM[200]
MyH 7Q1541PLMMUnknownMPD1[214]
MyH 7E1555KLMMReduced α-helical content of the rod domainHCM[218]
MyH 7R1588PLMMUnknownMPD1[213]
MyH 7L1591PLMMUnknownMPD1[219]
MyH 7L1597RLMMUnknownAxial myopathy, contractual myopathy[220]
MyH 7T1599PLMMUnknownMPD1[214]
MyH 7A1603PLMMUnknownMPD1[217]
MyH 7R1608PLMMUnknownCongenital myopathy, HCM[214]
MyH 7L1612PLMMUnknownMPD1[214]
MyH 71617-1617 del KLMMUnknownMPD1, DCM[214, 216]
MyH 7R1634SLMMUnknownDCM[208]
MyH 7A1636P
L1646P
R1662P		LMMUnknownMPD1[214]
MyH 7A1663PLMMUnknownMPD1[216]
MyH 71669-1669 del ELMMUnknownMPD1[214]
MyH 7V1691MLMMUnknownHCM[201]
MyH 7L1706PLMMUnknownMPD1[216]
MyH 7R1712WLMMUnknownHCM[210]
MyH 7L1723PLMMUnknownCCD[221]
MyH 71729-1729 del KLMMUnknownLaing distal myopathy[216]
MyH 7E1753KLMMUnknownHCM[210]
MyH 7A1766TLMMUnknownLVNC[222]
MyH 7E1768KLMMIncreased α-helical content of the rod domainHCM[200]
MyH 7S1776GLMMUnknownHCM[223]
MyH 7A1777TLMMUnknownHCM[201]
MyH 71784-1784 del KLMMUnknownMPD1, MSM[219, 224]
MyH 7L1793PLMMDestabilization of the thick filamentsHCM with MSD[225, 226]
MyH 71793-1793 del LLMMUnknownMPD1[214]
MyH 7E1801KLMMUnknownMPD1, DCM, HCM[214, 217]
MyH 7T1834MLMMUnknownHCM[200]
MyH 7R1845WLMMAlters interactions between filamentsMSM[227]
MyH 7E1856KLMMUnknownLate onset myopathy with cardiac involvement[228]
MyH 7E1883KLMMDestabilization of the thick filamentsHCM[226, 229]
MyH 7H1901LLMMAlters interactions between filamentsMSM[230]
MyH 7E1914KLMMUnknownDCM[214]
MyH 7N1918KLMMUnknownLVNC[231]
MyH 7T1929MLMMUnknownHCM[200]
MyH 7Stop1936WLMMUnknownMSM[232]
MyomesinAberrant splicing of exon 17aEH-motifPremature stop codon and truncated proteinMD1[233]
MyomesinV1490IIg12Reduced dimerizationHCM[234]
ObscurinR4344QIg58Loss of titin bindingHCM[235]
TitinS33705LfsX4TKUnknownLGMD2J[236]
TitinN34020TfsX9TKIncreased structural stability of TK, loss of interactions with proteins partners of TKMmD-HD[175]
TitinR34091WTKUnknownHMERF[23]
TitinR34175StopMIg1UnknownMmD-HD[175]
Titin32664-32665 del ins KMIg2UnknownHCM[237]
TitinP34617QinsX3MIs2UnknownCNM[238]
TitinR34637QMIg4UnknownDCM[239]
TitinA32606fsX7MIg5UnknownDCM[240]
TitinQ35176HfsX9MIg5Truncated titinMmD-HD (EOMFC)[241]
TitinQ35278StopMIs4UnknownMmD-HD[175]
TitinG35340VfsX65MIg6UnknownCNM[238]
Titin33710-33711 del ins KMIg6UnknownHCM[237]
TitinS35469SfsX11MIg7UnknownMmD-HD[175]
TitinK35524RfsX22MIs6UnknownMmD-HD (EOMFC)[241]
Titin32986-32987 del ins K MIg8UnknownDCM[240]
TitinM35859TMIs7UnknownARVC[242]
TitinS35883QfsX10MIs7UnknownTMD[243]
TitinQ35927–35931W del ins VKQKMIg10Truncated titinTMD, LGMD2J, MD[236, 244, 245]
TitinH35946PMIg10UnknownTMD[246]
TitinI35947NMIg10UnknownTMD[247]
TitinL35956PMIg10UnknownTMD[244]
TitinK35963NfsX9MIg10UnknownTMD, CNM[238, 243]
TitinQ35964StopMIg10Truncated titinTMD[243]
Note: nomenclature refers to the canonical full-length human isoforms; FHL-1, NP_001153174.1, sMyBP-C, AAI43503.1, MyH 3, NP_002461.2, MyH 6, NP_002462.2, MyH 7, NP_000248.2, myomesin, CAF18565.1, obscurin, CAC44768.1, titin, NP_001254479.2. HCM: hypertrophic cardiomyopathy, RBM: reducing body myopathy, XMPMA: X-linked myopathy with postural muscle atrophy, SPM: scapuloperoneal myopathy, RSS: rigid spine syndrome, EDMD: Emery-Dreifuss muscular dystrophy, DCM: dilated cardiomyopathy, DA-1: distal arthrogryposis type 1, LCCS4: lethal congenital contracture syndrome type 4, MPD1: Laing distal myopathy, CHD: congenital heart defect, CCD: central core disease, MSM: myosin storage myopathy, LVNC: left ventricular noncompaction, MD1: myotonic dystrophy type 1, LGMD2J: limb-girdle muscular dystrophy type 2J, MmD-HD: multiminicore disease with heart disease, HMERF: hereditary myopathy with early respiratory failure, CNM: centronuclear myopathy, EOMFC: early-onset myopathy with fatal cardiomyopathy, ARVC: arrhythmogenic right ventricular cardiomyopathy, TMD: tibial muscular dystrophy, MD: muscle disease, NLS: nuclear localization sequence, TK: titin kinase, MIgX: titin M-band IgX, MyH: myosin heavy chain, and LMM: light meromyosin.