Comparative sequencing of the proneurotensin gene and association studies in schizophrenia

Neurotensin (NT) is an endogenous tridecapetide(1) cleaved from a precursor proneurotensin/proneuromedin protein. NT localises within dopaminergic neurones in the mesocortical, mesolimbic and nigrostriatal systems(1-3) and it is now clear that NT can selectively modulate dopaminergic neurotransmission.(2-9) These anatomical and functional connections have led to the hypothesis that NT dysfunction might contribute to the pathogenesis of neuropsychiatric disorders in which disordered dopaminergic neurotransmission is suspected, particularly schizophrenia.(3) The latter hypothesis has been supported circumstantially by the observation that central administration of NT produces effects similar to those produced by the peripheral administration of atypical antipsychotics,(10,11) and ore directly by studies showing levels of NT in cerebral spinal fluid (CSF) is lower in schizophrenics than in controls.(12,13) To allow such hypotheses to be tested, we used denaturing high performance liquid chromatography (DHPLC)(14) to identify three sequence variants in the neurotensin gene (NTS) that might alter NT structure or expression. However, using a case-control study design and a novel genotyping system based upon a primer extension protocol and HPLC detection,(15) we found no evidence to support the hypothesis that variation in the proneurotensin gene contributes to susceptibility to schizophrenia.