Characterization of the human beta 4 nAChR gene and polymorphisms in CHRNA3 and CHRNB4

Most neuronal nicotinic acetylcholine receptors are heteropentamers, compos ed of a and P subunits. Mice lacking the alpha3 subunit and mice lacking bo th the beta2 and beta4 subunits, but not mice lacking the beta2 or beta4 su bunits alone, have a severe phenotype characterized by megacystis, failure of bladder strips to contract in response to nicotine, widely dilated ocula r pupils, growth failure, and perinatal mortality. The deficit in bladder c ontraction was also found in mice lacking only the beta4 subunit, although they did not develop megacystis. The major bladder phenotype resembles the human autosomal recessive disorder of megacystis-microcolon-hypoperistalsis syndrome (MMIHS). Based on the similarity of the mouse and human phenotype s, we initiated mutation analyses in the alpha3 and beta4 genes in MMIHS fa milies. The human gene encoding the beta4 subunit was fully characterized, including refinement of its mapping. Analysis of disease families and contr ols identified numerous genetic variants, including high-frequency polymorp hisms in both CHRNA3 and CHRNB4. Although no loss-of-function mutations hav e been identified to date, these genes remain strong candidates for involve ment in MMIHS, because various mutations might be obscured within the compl ex cluster of genes. Some of the markers presented here are valuable tools for analysis of the role of genetic variation in responses to nicotine and for characterization of various dysautonomic abnormalities.