Biochemical genetics of mouse histidine decarboxylase.

Mouse kidney histidine decarboxylase (HDC; E.C.4.1.1.22) has been used for a biochemical-genetic analysis of mammalian genetic regulatory mechanism. HDC is inducible by thyroxine and oestrogen, and is repressible by testosterone, and therefore provides an excellent system to study the multi-hormone control of a single product. An unusually large amount of genetic variation in HDC level was discovered by screening inbred and wild mice for (1) HDC activity, (2) sex-ratio , and (3) response to administered hormones. Analysis of some of the variants has revealed the HDC gene complex, [Hdc], on chromosome 2, and several unlinked loci with regulatory effects on HDC expression. The structural gene, Hdc-s, has been defined by two criteria, heat-stability and Km for the co-factor pyridoxal- 5t-phosphate. Two regulatory loci, Hdc-c and Hdc-e, have been demonstrated to be clustered at the structural locus to comprise a gene complex. Hdc-c determines kidney enzyme concentration and Hdc-e determines the response of the enzyme to oestrogen in females. Both loci are co-dominant, and antibody titration has shown that both act by controlling levels of HDC synthesis. [Hdc] has been precisely mapped and lies between ?2-microglobulin and pallid on chromosome 2. At least two unlinked genes are known to have regulatory effects on HDC expression. One of these is hti which determines the extent of HDC-thyroxine-inducibility. The gene is fully recessive and may have pleiotropic effects on other thyroxine-regulated proteins. Secondly, Tfm is an X-linked gene with regulatory effects on HDC expression. Tfm is the structural locus for the androgen receptor protein. Therefore, androgen-regulated processes are usually obliterated in Tfm/Y animals, but surprisingly HDC becomes testosterone-inducible. Other HDC variants have been found and analysis of these will probably reveal more regulatory loci, some of which may also map in the gene complex.