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 neu rones in the mesocortical, mesolimbic and nigrostriatal systems(1-3) and it is now clear that NT can selectively modulate dopaminergic neurotransmissi on.(2-9) These anatomical and functional connections have led to the hypoth esis that NT dysfunction might contribute to the pathogenesis of neuropsych iatric disorders in which disordered dopaminergic neurotransmission is susp ected, particularly schizophrenia.(3) The latter hypothesis has been suppor ted circumstantially by the observation that central administration of NT p roduces effects similar to those produced by the peripheral administration of atypical antipsychotics,(10,11) and ore directly by studies showing leve ls 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 sequen ce variants in the neurotensin gene (NTS) that might alter NT structure or expression. However, using a case-control study design and a novel genotypi ng system based upon a primer extension protocol and HPLC detection,(15) we found no evidence to support the hypothesis that variation in the proneuro tensin gene contributes to susceptibility to schizophrenia.