Deregulation of alternative processing of Calcitonin/CGRP-I pre-mRNA by a single point mutation.

The Calcitonin/CGRP-I (CALC-I) gene was one of the first examples of a cellular gene exhibiting alternative, tissue-specific processing of its primary transcript. Calcitonin (CT) mRNA is the predominant product in thyroid C-cells, whereas CGRP-I (Calcitonin Gene Related Peptide-I) mRNA is the main product in neurons of the central and peripheral nervous systems. Investigating the molecular mechanism underlying the alternative processing events, we have demonstrated that the CT-specific splice acceptor site is an intrinsical weak site due to usage of a uridine branch acceptor. The data presented in this report show that a single point mutation changing the uridine branch acceptor into a commonly preferred adenosine residue results in the predominant production of CT mRNA in otherwise CGRP-I mRNA-producing F9 cells. The results of the experiments implicate that the low efficiency of CT splicing, caused by usage of a uridine branch acceptor, allows the production of CGRP-I mRNA in neural cells.