Amino Acid Changes at Arginine 204 of Troponin I Result in Increased Calcium Sensitivity of Force Development

Abstract

Mutations in human cardiac troponin I (cTnI) have been associated with restrictive, dilated, and hypertrophic cardiomyopathies. The most commonly occurring residue on cTnI associated with familial hypertrophic cardiomyopathy (FHC) is arginine (R), which is also the most common residue at which multiple mutations occur. Two FHC mutations are known to occur at cTnI arginine 204, R204C and R204H, and both are associated with poor clinical prognosis. The R204H mutation has also been associated with restrictive cardiomyopathy (RCM). To characterize the effects of different mutations at the same residue (R204) on the physiological function of cTnI, six mutations at R204 (C, G, H, P, Q, W) were investigated in skinned fiber studies. Skinned fiber studies showed that all tested mutations at R204 caused significant increases in Ca2+ sensitivity of force development (ΔpCa50 = 0.22–0.35) when compared to wild-type (WT) cTnI. Investigation of the interactions between the cTnI mutants and WT cardiac troponin C (cTnC) or WT cardiac troponin T (cTnT) showed that all the mutations investigated, except R204G, affected either or both cTnI:cTnT and cTnI:cTnC interactions. The R204H mutation affected both cTnI:cTnT and cTnI:cTnC interactions while the R204C mutation affected only the cTnI:cTnC interaction. These results suggest that different mutations at the same site on cTnI could have varying effects on thin filament interactions. A mutation in fast skeletal TnI (R174Q, homologous to cTnI R204Q) also significantly increased Ca2+ sensitivity of force development (ΔpCa50 = 0.16). Our studies indicate that known cTnI mutations associated with poor prognosis (R204C and R204H) exhibit large increases in Ca2+ sensitivity of force development. Therefore, other R204 mutations that cause similar increases in Ca2+ sensitivity are also likely to have poor prognoses.

Clinical and functional characterization of a long survivor congenital titinopathy patient with a novel metatranscript-only titin variant

“…A previous study showed that a heterozygous mutation in the TPM2 gene resulted in a hypercontractile phenotype that is likely caused by increased calcium sensitivity of force generation [ 17 ]. Similar results are reported in patients with Tpm3.12 deletions and fast TnI mutations [ 18 , 19 ]. Increased calcium sensitivity of force generation can result in excessively sensitized cross-bridge cycling, leading to increased basal muscular tone [ 17 ].…”

The TNNI3 p.R186Q mutation is responsible for hypertrophic cardiomyopathy via promoting FASN-stimulated abnormal fatty acid metabolism

“…Unexpectedly, this study found that TNNI3 sarcomere gene mutations can both directly cause HCM, and also cause HCM by further changing the metabolism of cardiomyocytes. Moreover, no change was observed in the TC, TG, LDL or HDL levels in the serum of KI mice, while the corresponding indicators of TC and TG in the myocardial tissue increased, further confirming the myocardial specificity of cTnI [27] .…”

Genotype and Phenotype Analysis Using a Hypertrophic Cardiomyopathy-Associated Gene Panel in Turkish Cardiomyopathy Patients

“…Of the mutations on TNNI3, the mutation at the arginine residue at position 204 is the most common mutation associated with familial HCM. The R204H mutation is also associated with restrictive cardiomyopathy (RCM) [19]. In this study, it was reported for the first time that the R204C mutation can also lead to the RCM phenotype.…”