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Many bipolar affective disorder (BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the Bγ-regulatory subunit of the protein phosphatase 2A (PP2A-Bγ). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the Bγ subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K+ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-Bγ subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3β) is considered as an interesting target of lithium, the classical drug used in BD. GSK3β phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li+.The Pharmacogenomics Journal (2007) 7, 123–132. doi:10.1038/sj.tpj.6500400; published online 30 May 2006 [ABSTRACT FROM AUTHOR]

Reports on the development of a map of human chromosome which integrates physical and genetic data from the fusion of large collections of markers and corresponding yeast artificial chromosome (YAC) clones. Marker content analysis; Extension of YA C overlaps; Physical description of the construction of the map.

Analyzes the CEPH yeast artificial chromosomes (YAC) library containing 33,000 clones whose insert size was individually determined. Need for the identification of human disease genes with sets of ordered overlapping cloned genomic DNA fragments; Combination of mapping techniques to provide multiple sources of structural information for the clones.

Gene K51 probe isolated previously from the rat genomic library has been used to study the expression of its human counterpart by in situ hybridization and Northern blot analysis. A polyA-containing transcript of human gene K51 of 3 kb size has been detected in embryonic skin. The gene is also expressed in the epidermis of newborn humans and adults, but not in the adjacent mesenchymal tissues. Immunostaining with keratin antisera revealed predominantly earlier stage expression of K51 than cytokeratin markers. Sebaceous and sweat glands also contain cells expressing K51 gene. K51 expression was found in the cells of eight individual basal cell carcinomas tested, with the level of expression lower than in keratinocytes from normal human epidermis. We propose that K51 gene expression could serve as a convenient marker for the study of the process of skin keratinocyte development and the changes in this process associated with skin cancers and dysplasia. [ABSTRACT FROM AUTHOR]