Dopamine Modulates Adaptive Forgetting in Medial Prefrontal Cortex
Francisco Tomás Gallo, Maria Belen Zanoni, Azul Silva, Juan Facundo Morici, Magdalena Miranda, Michael C. Anderson, Noelia Weisstaub, Pedro Bekinschtein
Abstract
<h3>INTRODUCTION</h3> An intronic germline mutation in the <i>MSH2</i> gene, A→T at nt942+3, interferes with the exon 5 donor splicing mechanism leading to a mRNA lacking exon 5. This mutation causes typical hereditary non-polyposis colorectal cancer (HNPCC) and has been observed in numerous probands and families world wide. Recurrent mutations either arise repeatedly de novo or emanate from ancestral founding mutational events. The A→T mutation had previously been shown to be enriched in the population of Newfoundland where most families shared a founder mutation. In contrast, in England, haplotypes failed to suggest a founder effect. If the absence of a founder effect could be proven world wide, the frequent de novo occurrence of the mutation would constitute an unexplored predisposition. <h3>METHODS</h3> We studied 10 families from England, Italy, Hong Kong, and Japan with a battery of intragenic and flanking polymorphic single nucleotide and microsatellite markers. <h3>RESULTS</h3> Haplotype sharing was not apparent, even within the European and Asian kindreds. Our marker panel was sufficient to detect a major mutation arising within the past several thousand generations. <h3>DISCUSSION</h3> As a more ancient founder is implausible, we conclude that the A→T mutation at nt942+3 of <i>MSH2</i> occurs de novo with a relatively high frequency. We hypothesise that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenines, of which the mutated A is the first. It is by far the most common recurrent de novo germline mutation yet to be detected in a human mismatch repair gene, accounting for 11% of all known pathogenic<i>MSH2</i> mutations.