title: Alteration of branch site consensus sequence and enhanced pre-mRNA splicing of an NMDAR1 intron not associated with schizophrenia.
abstract: 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.
authors.affiliation: Division of Molecular Medicine, City of Hope National Medical Center, Duarte, California 91010-0269, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Hammond
authors.forename: Daniela
authors.initials: D
authors.lastname: Castanotto
authors.forename: Sharmon R
authors.initials: SR
authors.lastname: Rice
authors.forename: Vishwajit L
authors.initials: VL
authors.lastname: Nimgaonkar
authors.forename: Donna A
authors.initials: DA
authors.lastname: Wirshing
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Heston
authors.forename: Janet L
authors.initials: JL
authors.lastname: Sobell
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics*; D016022:Case-Control Studies; D016384:Consensus Sequence; D017931:DNA Primers; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007438:Introns; D008297:Male; D010957:Plasmids; D016133:Polymerase Chain Reaction; D012322:RNA Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*; D017384:Sequence Deletion; D014162:Transfection
chemical_list: D017931:DNA Primers; D012322:RNA Precursors; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate