A Mhc transgene carrying an amino acid substitution equivalent to the K146N (dominant) mutation in human beta-cardiac myosin heavy chain that causes hypertrophic cardiomyopathy. (FlyBase curator comment: the mutation in the Mhc gene is given as R146N in FBrf0240086, however analysis of the release 6.32 annotated gene model indicates the change to be R147N).
CG16770547AA
CGC>AAC
R147N | Mhc-PA; R147N | Mhc-PB; R147N | Mhc-PC; R147N | Mhc-PD; R147N | Mhc-PE; R147N | Mhc-PF; R147N | Mhc-PG; R147N | Mhc-PH; R147N | Mhc-PI; R147N | Mhc-PK; R147N | Mhc-PL; R147N | Mhc-PM; R147N | Mhc-PN; R147N | Mhc-PO; R147N | Mhc-PP; R147N | Mhc-PQ; R147N | Mhc-PR; R147N | Mhc-PS; R147N | Mhc-PT; R147N | Mhc-PU; R147N | Mhc-PV
R146N
Analogous K146N mutation in human MYH7 implicated in hypertrophic cardiomyopathy; mutation carried on in vitro construct.
The disease model uses Mhc[R146N] in either a Mhc[10]/Mhc[10] or Mhc[1]/+ background.
adult heart, with Mhc10
M band | adult stage | progressive, with Mhc10
myofibril | adult stage | progressive, with Mhc10
myofilament | adult stage | progressive, with Mhc10
Z disc | adult stage | progressive, with Mhc10
Indirect flight muscles in Mhc10/Mhc10, MhcR146N/MhcR146N females show normal sarcomere organization at late pupal stage and in 2h-old adults, minor disruptions of thick and thin filament packing in 2-days old adults, and disorder in myofibril morphology in 7-days old adults, including gaps in the hexagonal packing of thick and thin filaments and disruption in the Z- and M-lines, as compared to controls. These muscles also show significantly decreased power generation and work, significantly increased active tension, but do not show a significant change in passive tension, as compared to controls; under optimal power producing conditions, there are further significant decreases in power generation, net work (likely due to decreased work generated:work absorbed ratio), and in relative muscle length amplitude, as compared to controls. These muscle defects are associated with a progressive decrease in flight index and a lower wing beat frequency, as compared to controls. Mhc10/Mhc10, MhcR146N/+ individuals display similar, albeit more modest, flight ability defects and indirect flight muscle morphology and performance defects.
The hearts of Mhc10/Mhc10, MhcR146N/+ individuals display significant decreases in cardiac dimensions (diastolic and systolic diameters) and in fractional shortening, and a significant increase in systolic interval, but do change in heart period, as compared to controls; the heart has an essentially normal myofibrillar integrity and organization in 1-week old adults, but displays myofibrillar discontinuities in 3-weeks old adults, as compared to controls; cardiomyocyte thickness in both young and aged mutant adults shows no statistically significant differences, as compared to controls.