FIGURE 53-1. The human calcitonin (CT) gene family: organization of genes, mRNAs, and their hormone precursors. Based on their nucleotide sequence homologies, five genes belong to this family: CALC-I (CT/calcitonin gene–related peptide-I [CGRP-I]), CALC-II (CGRP-II), CALC-III, CALC-IV (amylin), and the CALC-V (adrenomedullin [ADM]) genes. Two structural features that are essential for full functional activity are conserved between the peptides: They contain two N-terminal cysteines that form a disulfide bridge resulting in an N-terminal loop and a C-terminal amide. A, The CALC-I primary transcript is processed into three different mRNAs: CT, CT-II, and CGRP-I mRNAs. The different products are generated by the inclusion or exclusion of exons by a mechanism termed splicing. Exons I–III are common for all mRNAs. Exon IV codes for CT, and exon V codes for CGRP-I. CT mRNA includes exons I + II + III + IV. CT-II mRNA includes exons I + II + III + IV (partial) + V + VI. CGRP-I mRNA is composed of exons I + II + III + V + VI. Each mRNA codes for a specific precursor. CT mRNA codes mainly for an N-terminal region, mature CT, and a specific C-terminal peptide (i.e., katacalcin, PDN-21, or calcitonin carboxy-terminal peptide-I [CCP-I]) that consists of 21 amino acids (aa). The N-terminal region includes a signal peptide of 25 amino acids and an N-terminal peptide of 57 amino acids (i.e.,aminoprocalcitonin [NProCT] or PAS-57). The CT-II precursor differs from the CT-I precursor by its specific C-terminal peptide, CCP-II. CCP-I differs from CCP-II by its last eight amino acids. CGRP-I mRNA codes for an N-terminal region, mature CGRP-I, and a cryptic peptide. The commitment of primary transcript in the different splicing pathways is determined, in part, by a tissue specificity. Although some overlap is seen, the CGRP-I mRNA is expressed mainly in nervous tissue, and CT mRNA is the major mRNA product in thyroid tissue and other tissues, whereas CT-II was found to be expressed in liver. B, The CALC-II gene codes only for a CGRP-II precursor. Its organization is similar to that of the CALC-I gene, containing 6 exons. Sequence homologies are important. Examination of the exon IV–like region of CALC-II indicates that CT mRNA is unlikely. Splicing at the site equivalent to the exon III–exon IV junction in human CT mRNA would result in a stop codon within the reading frame of the precursor polypeptide. Although CALC-II appears to be a pseudogene for CT, it is a structural gene for CGRP-II. The CGRP-II hormone differs from CGRP-I by three amino acids. C, The CALC-III gene contains only two exons. Their sequences have homologies with exon II and III of the CALC-I and CALC-II genes. The CALC-III gene does not seem to encode a CT- or CGRP-related peptide hormone and is probably a pseudogene that is not translated into a protein. D, The CALC-IV gene codes for a precursor containing the amylin peptide. This gene contains only three exons. The third exon codes for amylin. This 37-amino-acid peptide has marked homology with the CGRP peptides. The suggestion has been made that the CT and CGRP exons are derived from a primordial gene and that the different CT/CGRP/ADM/amylin genes have arisenby duplication and sequence-divergent events. E, The CALC-V gene is translated into ADM. This gene contains four exons. ADM is coded by the fourth exon. The amino-terminal peptides, encoded by exons II and III, also have some bioactivity.