19 DNA Damage and Human Disease

Abstract

The inactivation of genes in germ-line cells that encode proteins required for the repair (or other processing) of DNA damage can result in hereditary diseases that are characterized by an abnormal mutational burden in the somatic cells of progeny. Most of these diseases are inherited in an autosomal recessive fashion and manifest obvious phenotypes only in the homozygous mutant state. Hence, they are relatively rare as clinical entities. Nonetheless, their study has provided important information on cellular responses to DNA damage in humans and has yielded significant inroads into our understanding of disease pathogenesis.

The number of human hereditary diseases with known or suspected defects in biological responses to DNA damage has grown considerably (see Appendix, Table VI) (see Friedberg et al. 2005). Space restraints dictate incomplete discussions of these. Hence, this chapter considers only the more commonly encountered and best-characterized examples. Readers should also be aware that gene replacement technology has facilitated the generation of an impressive collection of mutant mouse strains defective in genes required for or involved in biological responses to DNA damage (Friedberg and Meira 2006). These mouse models are not considered here. A comprehensive list of references is also limited by space constraints. The interested reader is referred to a recent textbook (Friedberg et al. 2005) in which the subject of this chapter is extensively discussed. This reference is cited in numerous instances in the text, with apologies to the authors of omitted primary publications.

DISEASES ASSOCIATED WITH DEFECTIVE NUCLEOTIDE EXCISION REPAIR
Nucleotide excision repair...