title: Human caspase 12 has acquired deleterious mutations.
abstract: Caspase 12 has been cloned from rodent cells, in which it mediated apoptosis in response to endoplasmic reticulum stress. Based on experiments with murine cells it was suggested that this caspase plays a central role in the pathogenesis of Alzheimer's disease. By alignment of the murine caspase 12 cDNA with the human genome sequence we localized the human caspase 12 gene at a single locus within the caspase 1/ICE gene cluster on chromosome 11q22.3. RT-PCR and molecular cloning revealed that nine alternatively spliced transcripts of this gene are expressed. A frame shift mutation and a premature stop codon which is present in all splice variants preclude the expression of a full length protein. An additional loss-of-function mutation within the SHG box, a critical site in caspases, prohibits any proteins, if they are produced, from acting catalytically. Based on our data we conclude that functional caspase 12 is lost in humans and that it can therefore not play a role in Alzheimer's disease.
authors.affiliation: Department of Dermatology, University of Vienna Medical School, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Fischer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Koenig
authors.forename: Leopold
authors.initials: L
authors.lastname: Eckhart
authors.forename: Erwin
authors.initials: E
authors.lastname: Tschachler
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D053454:Caspase 12; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D012333:RNA, Messenger / Q000096:biosynthesis; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D014018:Tissue Distribution
chemical_list: D012333:RNA, Messenger; C506444:CASP12 protein, human; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020169:Caspases