Human Troponin Genes: Transcriptional Regulation and Chromosomal Organization

The troponin complex forms the calcium-sensitive molecular switch which regulates striated muscle contraction in response to alterations in intracellular calcium concentration. It is located on the thin filament of the sarcomere and is composed of three subunits: troponin C, the calcium binding subunit; troponin T, which is involved in the attachment of the complex to tropomyosin; and troponin I, the inhibitory subunit. Multiple isoforms of each of these subunits have been identified (see table 1) which are expressed with distinct tissue-specificity and developmental regulation [1,2]. In the case of troponin I, three isoforms have been identified in vertebrate striated muscle and in the adult these are expressed in cardiac muscle, slow skeletal muscle and fast skeletal muscle respectively. In the adult heart, cardiac troponin I is the only troponin I isoform detected in the bulk of the myocardium. However, during development the predominant isoform expressed is slow skeletal troponin I [2]. We have previously documented aspects of troponin expression in the human heart [3–6] and demonstrated a developmental switch in troponin I expression during human development. Analysis of mRNA and protein levels suggests that the increase in expression of the cardiac troponin I gene seen in late fetal stages in man is due to an increase in transcription. Here, we present data on the basic machinery required for the expression of the human cardiac troponin I gene. In other studies we have analyzed the organization of the troponin gene families and revealed that the six human genes encoding the different troponin I and T isoforms are organized as paralogous pairs located at three different chromosomal sites. Analysis of the pair comprized of the cardiac troponin I and slow skeletal troponin T genes reveals that they are organized head to tail and lie within 3 kb of each other. Close physical linkage raises questions concerning the evolution of these two troponin gene families, for their regulation and for the analysis of mutations suspected to result in cardiomyopathy.