Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in schizophrenic patients

Recent studies have revealed that an orphan receptor gene of the steroid/thyroid hormone nuclear receptor superfamily, the Nurr1 gene, is essential for the neurogenesis and differentiation of dopaminergic neurons in the midbrain of mice. Transgenic mice lacking the Nurr1 gene soon die after birth and are devoid of dopaminergic neurons in the midbrain. Heterozygous mice survive postnatally without obvious locomotor deficits; however, they have increased vulnerability to dopaminergic neurotoxin 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In view of the importance of dopamine neurotransmission in brain function, we were interested to know if the human homologous gene of murine Nurr1, the NR4A2 gene, may play a role in the pathogenesis of schizophrenia. We systematically sequenced all the exons of the human NR4A2 gene to search for molecular variants in a cohort of Chinese schizophrenic patients from Taiwan. Two molecular variants were identified: a G-insertion in intron 6 (designated IVS6+17∼+18insG), and a G-deletion in the untranslated exon 1 (designated c.-469delG). The IVS6+17∼+18insG is a polymorphic one; further case control study, however, did not reveal association of this polymorphism with schizophrenia. The c.-469delG is a rare variant found in two unrelated patients among 177 schizophrenic patients, but not in 130 nonpsychotic controls. The result suggests that the c.-469delG and possibly other variants of the NR4A2 gene may be of relevance to the complex factors involved in the pathogenesis of schizophrenia.