Molecular characterization of human TRPM‐2/clusterin, a gene associated with sperm maturation, apoptosis and neurodegeneration

The TRPM‐2/clusterin gene and its cognate protein has been characterized in a number of species. Although the functional role, or roles, of the TRPM‐2/clusterin protein remains to be firmly established, the gene has been implicated in a variety of physiological processes, including sperm maturation, lipid transport, membrane remodelling and inhibition of the complement cascade. TRPM‐2/clusterin is induced de novo during the regression of the prostate and other hormone‐dependent tissues after hormone ablation, and is over‐expressed in several human neurodegenerative diseases including Alzheimer's disease, epilepsy and retinitis pigmentosa. We describe the genomic structure of the human TRPM‐2/clusterin gene which is organized into nine exons, ranging in size from 47 bp (exon I) to 412 bp (exon V), spanning a region of 16580 bp. Comparison with sequences registered in the databases shows that it has extensive similarity to the human protein designated as SP‐40,40 or complement‐lysis inhibitor (CLI), a protein that appears to block the membrane‐attack complex of complement. However, the cDNA sequences reported for SP‐40,40 and CLI diverge significantly in the 5′ untranslated region of the mRNA (coded for by exon I), raising the possibility that the TRPM‐2/clusterin gene is present in the human genome as a small multi‐gene family or that there are several alternate exon I sequences in the TRPM‐2 gene. Southern analysis and fluorescent in situ hybridization suggest that the clusterin gene is a single‐copy gene, and that, if alternative exon I sequences are present in the genome, they lie outside of the λ clones that have been characterized. Analysis of the promoter region of the human TRPM‐2/clusterin gene shows many similarities to the rat TRPM‐2/clusterin promoter including a putative control region containing several potential regulatory elements that may regulate the complex tissue‐specific control of the gene which must be constitutively expressed in some tissues but is inducible in others.