GENOMIC STRUCTURE AND CHROMOSOMAL LOCALIZATION OF A HUMAN MYOINOSITOLMONOPHOSPHATASE GENE (IMPA)

Manic-depressive illness is a serious psychiatric disorder that in man y, but far from all, patients can be treated with lithium. The main ca uses for discontinuation of lithium therapy are unpleasant or serious side effects and lack of response. The reason for the striking variati on in clinical efficacy of lithium treatment among bipolar patients is not known. The enzyme myoinositol monophosphatase (IMPase) has been p ostulated as a target for the mood-stabilizing effects of lithium, but variation in the coding region of the human IMPA gene encoding IMPase activity has not been observed in manic-depressive patients (Steen et al., Pharmacogenetics, 1996, 6, 113-116). It is nevertheless conceiva ble that polymorphisms or mutations in the noncoding regions of this g ene could influence the lithium response in psychiatric patients. As a first step in investigating this possibility, we here report the geno mic structure of the human IMPA gene. The gene is composed of at least nine exons and covers more than 20 kb of sequence on chromosome 8q21. 13-q21.3. In the 3'-untranslated part of the gene, we observed a polym orphism (a G to A transition) and also two short sequences similar to the inositol/cholin-responsive element consensus. Finally, we postulat e that two additional IMPA-like transcripts originate from the human g enome, one from a position close to IMPA itself on chromosome 8 and th e other from chromosome 18p. Our data may contribute to the identifica tion of genetic factors involved in the pathogenesis and determination of treatment response in manic-depressive illness. (C) 1997 Academic Press.