Table 1. Phenotypic heterogeneity of sarcomeric genes and differential changes of mutant protein function (8,9,12-16).
| Gene | Protein | DCM | Function | HCM | Function | Other allelic disorders |
|---|---|---|---|---|---|---|
| Thick filament | ||||||
| MYH7 | Cardiac β myosin heavy chain | yes | ↓maximal force generation ↓contractility ↓velocity of actin sliding |
yes | ↑maximal force generation ↑Ca++ sensitivity |
Laing distal myopathy, myosin storage myopathy, scapuloperoneal myopathy, left ventricular non-compaction, endocardial fibroelastosis |
| MYH6 | Cardiac α myosin heavy chain | yes | * | yes | * | Atrial septal defect |
| MYL2 | Regulatory myosin light chain | Not described | yes | ↑Ca++ sensitivity | ||
| MYL3 | Essential myosin light chain | Not described | yes | ↑Ca++ sensitivity | ||
| MYBPC3 | Cardiac myosin-binding protein C | yes | yes | Hypertrophy Diastolic dysfunction | ||
| Thin filament | ||||||
| TNNT2 | Cardiac Troponin T (cTnT) | yes | ↓myofibrillar function ↓Ca++ sensitivity |
yes | ↑myofibrillar function ↑Ca++ sensitivity |
Restrictive cardiomyopathy |
| TNNTI3 | Cardiac troponin I (cTnI) | yes | ↓myofibrillar function ↓binding to cTnT |
yes | ↑myofibrillar function ↑Ca++ sensitivity |
Restrictive cardiomyopathy (↑↑Ca++ sensitivity) |
| TNNC1 | Cardiac troponin C (cTnC) | yes | ↓myofibrillar function ↓Ca++ sensitivity ↓PKC effect |
yes | ↑myofibrillar function | |
| TPM1 | Tropomyosin 1 alpha chain |
yes | ↓Ca++ sensitivity ↓maximum force |
yes | ↑myofibrillar function ↑Ca++ sensitivity |
|
| ACTC1 | α-Cardiac actin | yes | ↓α-cardiac actinin (Z-disk) affinity ↓force transmission |
yes | Impaired actomyosin binding | Restrictive cardiomyopathy |
| Titin filament and Z-disk | ||||||
| TTN | Titin | yes | ↓biding to actinin and Tcap | yes | ↑biding to actinin and Tcap | Tibialis muscular dystrophy or Udd distal myopathy; hereditary myopathy with early respiratory failure (HMERF); recessive limb-girdle muscular dystrophy type 2J (LGMD2J) |
| TCAP | Titin-cap or telethonin | yes | ↓biding to titin, MLP and myozenin-2 | yes | ↑biding to titin, and myozenin-2 | Limb-girdle muscular dystrophy type 2G (LGMD2G) |
| ANKRD1 | Cardiac ankyrin repeat protein (CARP) | yes | ↓biding to talin1 | yes | ↑biding to titin and myopalladin | Total anomalous pulmonary venous return (↑expression) |
| LDB3 | Cypher/ZASP | yes | Cytoskeletal disarray, ↓PKC affinity | Not described | Left ventricular non-compaction, myofibrillar myopathy | |
| CSRP3 | MLP | yes | yes | ↓biding to actinin | ||
| MYOZ2 | Myozenin-2 | Not described | yes | |||
| OBSCN | Obscurin | Not described | yes | ↓biding to titin | ||
*
Legend: β myosin heavy chain mutations found in HCM and DCM were studied in a myosin heavy chain of knock-in mouse models