Pleiotropy revisited: molecular explanations of a classic concept

As commonly used, pleiotropy refers to multiple effects on phenotype of a single mutant gene. The importance of this concept to medical genetics has waxed and waned since its formulation soon after the rediscovery of Mendel's laws. Initially, the view that all aspects of a phenotype, and hence all manifestations of a mendelian syndrome, derive from a single function (or dysfunction) of a mutant allele gained ascendancy. Support for the importance of pleiotropy gradually diminished, and reached a low point in the 1940s with the one gene-one enzyme hypothesis. Studies of mammals and humans with heritable disorders of connective tissue sustained the notion that "genuine" pleiotropy probably did not exist. However, the demise of the relevance of pleiotropy was premature. Detailed understanding of gene organization, expression, and mutation indicates several mechanisms, such as multifunctional proteins, alternative splicing of messenger RNA, and overlapping coding sequences, through which genuine pleiotropy likely occurs in normal development and function, in mendelian syndromes, and in conditions due to somatic mutation. Furthermore, a broad definition of pleiotropy is warranted to subsume syndromes caused by abnormal function of contiguous genes, such as through large deletions, mutation of regulatory elements that coordinate expression, or less clearly understood "position effects." Thus, the use of pleiotropy in the context of aneuploidy syndromes is not inappropriate.