Alteration of branch site consensus sequence and enhanced pre‐mRNA splicing of an NMDAR1 intron not associated with schizophrenia

Aberrant splicing of pre‐mRNA is recognized to account for a significant minority of disease‐causing mutations. The N‐methyl‐D ‐aspartate receptor (NMDA) subunit gene R1 (NMDAR1) is alternatively spliced to produce eight length variants. In an examination of the NMDAR1 as a candidate gene in schizophrenia, a presumed microdeletion/insertion (del/ins) was observed in intron 10 of an African‐American male near a weak putative branch‐site consensus sequence. Although exon 10 is not known to be alternatively spliced, the del/ins was posited to alter splicing efficiency. If splicing were abolished and intron retention occurred, an in‐frame translation product of more than 250 amino acids was predicted. To explore splicing efficiency, mini genes were examined through primer‐extension analyses in NIH293 embryonic kidney cell cultures. Rather than disruption of splicing, the del/ins allele exhibited a fivefold enhancement in splicing. In an association analysis with additional schizophrenic cases and unaffected controls, all of African‐American descent, the mutant allele was observed at equivalent frequencies. A family study also did not support cosegregation of the variant allele with psychiatric disease. © 2002 Wiley‐Liss, Inc.