Calcium binding proteins of the S100 family play a central role in many intra- and extracellular processes and abnormal expression was observed in various tumors and human diseases. We have identified a unique new member of this gene family: S100A16 which is the S100 protein widest distributed in human and which is highly conserved in mammals. Up-regulation of S100A16 was found in many tumors implying a central cellular function related to malignant transformation. The gene was composed of four exons, two of which alternatively initiated transcription. Three different transcripts suggested a complex regulation of the S100A16 gene. Moreover, CAG repeats were identified in the transcribed region which might be associated with diseases of the nervous system. All human transcripts encoded the same, typically small S100 protein of 103 amino acids containing the S100-specific motif of two distinct EF-hands. S100A16 was mapped within the S 100 gene cluster on human chromosome 1q21, a region that is frequently rearranged in tumors. (C) 2003 Elsevier Inc. All rights reserved.