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Fine-mapping reveals novel alternative splicing of the dopamine transporter.

journal contribution
posted on 05.12.2010, 00:00 by Michael E. Talkowski, Kathleen L. McCann, Michael Chen, Lora McClain, Mikhil Bamne, Joel Wood, Kodavali V. Chowdari, Annie Watson, Konasale M. Prasad, George Kirov, Lyudmilla Georgieva, Draga Toncheva, Hader Mansour, David A. Lewis, Michael Owen, Michael O'Donovan, Panagiotis Papasaikas, Patrick Sullivan, Douglas Ruderfer, Jeffrey K. Yao, Sherry Leonard, Pramod Thomas, Fabio Miyajima, John Quinn, Antonio-Javier LopezAntonio-Javier Lopez, Vishwajit L. Nimgaonkar

The dopamine transporter gene (SLC6A3, DAT) has been implicated in the pathogenesis of numerous psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). We previously detected association between SZ and intronic SLC6A3 variants that replicated in two independent Caucasian samples, but had no obvious function. In follow-up analyses, we sequenced the coding and intronic regions of SLC6A3 to identify complete linkage disequilibrium patterns of common variations. We genotyped 78 polymorphisms, narrowing the potentially causal region to two correlated clusters of associated SNPs localized predominantly to introns 3 and 4. Our computational analysis of these intronic regions predicted a novel cassette exon within intron 3, designated E3b, which is conserved among primates. We confirmed alternative splicing of E3b in post-mortem human substantia nigra (SN). As E3b introduces multiple in-frame stop codons, the SLC6A3 open reading frame is truncated and the spliced product may undergo nonsense mediated decay. Thus, factors that increase E3b splicing could reduce the amount of unspliced product available for translation. Observations consistent with this prediction were made using cellular assays and in post-mortem human SN. In mini-gene constructs, the extent of splicing is also influenced by at least two common haplotypes, so the alternative splicing was evaluated in relation to SZ risk. Meta-analyses across genome-wide association studies did not support the initial associations and further post-mortem studies did not suggest case-control differences in splicing. These studies do not provide a compelling link to schizophrenia. However, the impact of the alternative splicing on other neuropsychiatric disorders should be investigated. © 2010 Wiley-Liss, Inc.