Before duplication the ancestral sarcomeric α-actinin had the functions of both ACTN2 and ACTN3 in terms of tissue expression and functional isoforms. ❋ Unknown (2009)
Lek M, Quinlan KG, North KN 2009 The evolution of skeletal muscle performance: gene duplication and divergence of human sarcomeric alpha-actinins. ❋ Unknown (2009)
Using sarcomeric α-actinin as an example, after duplication of a gene capable of multiple interactions/functions, there are two possible distinct scenarios besides gene loss. ❋ Unknown (2009)
An alternative hypothesis explored here is that multiple CM mutant proteins cause allele-specific combinatorial primary effects that uniquely alter sarcomeric function and are not necessarily linked directly to total mutant gene dosage. ❋ Jennifer Davis Et Al. (2010)
(A) Double Activating Allele Model: the positive sloping gradient represents the additive slowing of relaxation and heightened severity of diastolic dysfunction that occurs with the combination of two activating mutant alleles from different sarcomeric loci. ❋ Jennifer Davis Et Al. (2010)
CM sarcomeric proteins can directly cause thin filament deactivation ❋ Jennifer Davis Et Al. (2010)
(B) Double Deactivating Allele Model: the negative sloping gradient represents the predicted additive consequence to accelerate relaxation and reduce contractility that occurs with the combination of two deactivating mutant alleles from different sarcomeric loci. ❋ Jennifer Davis Et Al. (2010)
Collectively, these data demonstrate that within the context of the physiologically intact unloaded myocyte coexpressing a deactivating and an activating sarcomeric allele from different loci partially mitigates the primary effects elicited by each mutant alone. ❋ Jennifer Davis Et Al. (2010)
We propose all CM sarcomeric can be incorporated into the model as they all fundamentally effect myofilament regulation ❋ Jennifer Davis Et Al. (2010)
First, this family of sarcomeric proteins is highly amenable to acute genetic engineering and structure-function studies ❋ Jennifer Davis Et Al. (2010)
While this activating activating/deactivating paradigm should be tested on other mutant sarcomeric alleles, support for our model can be derived from double heterozygous patients with a combined myosin and troponin mutation that have early morbidity and an increased incidence of surgical treatment and sudden cardiac death, as well as the increased mortality in the MyHC R403Q + G203S cTnI double heterozygous mice described above ❋ Jennifer Davis Et Al. (2010)
Contributing to this genetic complexity and clinical heterogeneity is the emergence of a cohort of patients that are double or compound heterozygotes who have inherited two different CM mutant alleles in the same or different sarcomeric gene. ❋ Jennifer Davis Et Al. (2010)
Hundreds of mutations in eleven different sarcomeric genes have co-segregated with a cardiomyopathy phenotype ❋ Jennifer Davis Et Al. (2010)
Adding to the complexity of CM is the realization there are ~467 CM-linked mutant alleles that have been reported in eleven different sarcomeric genes ❋ Jennifer Davis Et Al. (2010)
Using experimental data from activating and deactivating sarcomeric CM mutants obtained here and elsewhere as foundations, a working model was developed to promote predictive insights into myocyte function of the theoretically possible tens of thousands of compound CM combinations. ❋ Jennifer Davis Et Al. (2010)
Integrin-mediated adhesion maintains sarcomeric integrity. ❋ Unknown (2010)
Thus, our working hypothesis is that altered biophysical properties of double mutant sarcomeric proteins could interact to either heighten or mitigate the functional cellular outcomes of either mutant allele when studied in isolation. ❋ Jennifer Davis Et Al. (2010)
The mechanistic basis for additive/mitigating effects cannot be solely due to total mutant gene dosage alone, but also appears to be highly dependent on the population and location of double mutant regulatory units along the thin filament and the biophysical properties of the effected sarcomeric protein in terms of the activating/deactivating nature and the strength of these mutant alleles. ❋ Jennifer Davis Et Al. (2010)
This formula is calculated for total number of mutations within each sarcomeric loci and then summated to equal 33,737 possible genotypes. ❋ Jennifer Davis Et Al. (2010)
The activation properties of numerous single sarcomeric mutants in both the thick and thin filament have already been characterized ❋ Jennifer Davis Et Al. (2010)
