The calcitonin (CT) gene is alternatively expressed in a tissue-specific fashion producing either the calcium regulatory hormone CT in the thyroid or the neuropeptide calcitonin gene related peptide (CGRP) in the brain. In medullary carcinoma of the thyroid both peptides are produced. We present here evidence for the existence in the human genome of a second CT gene, which is also expressed in human medullary thyroid carcinoma. This gene encodes a second human CGRP, differing from the known human CGRP in 3 of the 37 amino acids.

Islet or insulinoma amyloid polypeptide (IAPP) is a 37 amino acid polypeptide isolated from pancreatic amyloid. Here, we describe the isolation and partial characterization of the human gene encoding IAPP. The DNA sequence predicts that IAPP is excised from a larger precursor protein and that its carboxy-terminus is probably amidated. The predicted normally occurring IAPP is identical to the reported polypeptides isolated from pancreatic amyloid, except for the amidated carboxy-terminus.IAPP specific polyadenylated RNAs of 1.6 kb and 2.1 kb are present in human insulinoma RNA. The human IAPP gene is located on chromosome 12.

Recently, we have reported the isolation of cDNA encoding a second human calcitonin gene-related peptide (hCGRP-II) [(1985) FEBS Lett. 183, 403407j. In this report we describe the isolation and characterization of the gene encoding hCGRP-II. This gene, designated CALC-II, is structurally closely related to the known CALC-I gene encoding human calcitonin (hCT) and hCGRP-I. In constrast to CALC-I, CALC-II does not seem to be alternatively expressed. The formation of a second, hCT-like mRNA by differential splicing of CALC-II transcripts is unlikely in view of the structure of CALC-II, and could not be demonstrated in tissues known to express CALC-I and CALC-II.

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Nucleotide sequence analysis of part of the human calcitonin (hCT) gene revealed the presence of a region with 90% homology to the region in the corresponding rat gene encoding calcitonin gene related peptide (CGRP). Analysis of RNA isolated from human medullary thyroid carcinoma (MTC) indicated that in these tumors mRNA hybridizing to hCT specific probe, mRNA hybridizing to hCGRP specific probe and larger RNA species hybridizing to both hCT and hCGRP probes occur. These results suggest that alternative splicing of the primary transcripts of the human CT gene may result in hCT or hCGRP mRNA.

A molecular probe containing a 584 base pairs sequence corresponding to part of the human calcitonin mRNA was used for the chromosomal assignment of the calcitonin gene. Restriction endonuclease analysis of DNA from human-Chinese hamster and human-mouse somatic cell hybrids, including some containing a translocation of human chromosomes, placed the calcitonin gene in the p14----qter region of chromosome 11. Analysis of human DNA showed that the calcitonin gene has a polymorphic site for restriction endonuclease TaqI.

A second human calcitonin/calcitonin gene related peptide (hCT/CGRP) gene has been identified. This second hCT/CGRP gene has been shown to contain sequences highly homologous to exons 3, 5 (CGRP-encoding), and 6 of the first hCT/CGRP gene, but sequences closely related to exon 4 (CT-encoding) could not be demonstrated. Southern blot hybridization analysis of DNA from human-rodent somatic cell hybrids showed that the second hCT/CGRP gene is located in the q12-pter region of chromosome 11. The first hCT/CGRP gene has previously been assigned to the p13-p15 region of chromosome 11.