Thin filament mutations: developing an integrative approach to a complex disorder

Abstract

Sixteen years ago, mutations in cardiac troponin (Tn)T and α-tropomyosin were linked to familial hypertrophic cardiomyopathy, thus transforming the disorder from a disease of the β-myosin heavy chain to a disease of the cardiac sarcomere. From the outset, studies suggested that mutations in the regulatory thin filament caused a complex, heterogeneous pattern of ventricular remodeling with wide variations in clinical expression. To date, the clinical heterogeneity is well matched by an extensive array of nearly 100 independent mutations in all components of the cardiac thin filament. Significant advances in our understanding of the biophysics of myofilament activation, coupled to the emerging evidence that thin filament linked cardiomyopathies are progressive, suggests that a renewed focus on the most proximal events in both the molecular and clinical pathogenesis of the disease will be necessary to achieve the central goal of using genotype information to manage affected patients. In this review, we examine the existing biophysical and clinical evidence in support of a more proximal definition of thin filament cardiomyopathies. In addition, new high-resolution, integrated approaches are presented to help define the way forward as the field works toward developing a more robust link between genotype and phenotype in this complex disorder.

Figure 1

An Atomistic Model of the Human Cardiac Thin Filament in the Ca²⁺-activated State Yellow = cTnT; Blue= cTnI; Red = cTnC; Green = α – Tropomyosin ; Silver/Gray = actin filament. For details of model development please see Data Supplement.

Figure 2

The 3-State Model of Myofilament Activation The 3 average positions of TM are depicted. In the Blocked State (red), TM resides at the outer actin domain, Ca²⁺ binding to cTnC results in an azimuthal shift to the weakly bound Closed State (yellow) in the actin inner domain and myosin binding drives the final shift to the force-producing Open state (green).

Figure 3

Cardiac TnI Exons, Structure and Functional Domains Listed mutations are discussed in text, ** denotes Ser 23/24 PKA-dependent phosphorylation sites. Mutations in grey have been linked to primary DCM and mutations in italic have been linked to RCM. Inset: cTnI secondary structure

Figure 4

Distribution of HCM and DCM – linked Mutations in the cTnT N-terminal Domain Residues 105 to 220 of cTnT are shown. This region of cTnT is highly conserved and the structure of the protein between residues 150 – 200 is poorly defined. Mutations that lead to hypertrophic or non-dilated ventricular remodeling are shown in gray and are contiguous to DCM -causing mutations (black).

Figure 5

Human Cardiac cTnT Exons, Structure and Functional Domains Listed mutations are discussed in text, Mutations in blue have been linked to DCM. Undefined structures (as per Takeda, et al) are red and black, gray boxes represent clusters of known mutations. Inset: Predicted cTnT secondary structure

Figure 6

Human Cardiac TM Exons, Structure and Periods Grey shaded periods represent the two primary actin-binding regions. Listed mutations are discussed in text, Mutations in blue have been linked to DCM. Inset: Predicted TM secondary structure, P2 = Period 2, P5 = Period 5 (regions where mutations are clustered)