Genetic Diseases

Genetic diseases are traditionally classified as Mendelian or multifactorial diseases. Mendelian diseases are due to mutations in single genes; multifactorial diseases arise as a result of the joint action of multiple genetic and environmental factors.

Molecular analyses have revealed that a wide variety of mutational changes underlie Mendelian diseases: “microlesions,” such as single base-pair substitutions, deletions, insertions, or duplications involving one to a few base pairs; and “gross lesions,” such as whole-gene or multigene deletions, complex rearrangements, and large insertions and duplications. Microlesions dominate the spectrum of Mendelian diseases (Krawczak and Cooper 1997).

At the functional level, mutations can be classified as causing either a loss of function or the gain of a new function. Normal gene function can be abolished by some types of point mutations, partial or total gene deletions, disruption of the gene structure by translocations or inversions of the genetic material, and so on. In most cases, loss-of-function mutations in enzyme-coding genes are recessive, because 50% of the gene product is usually sufficient for normal functioning. Loss-of-function mutations in genes that code for structural or regulatory proteins, however, result in dominant phenotypes through haploinsufficiency (a 50% reduction in the gene product in the heterozygote is insufficient for normal functioning but is compatible with viability) or through dominant negative effects (the product of the mutant gene not only loses its own function but also prevents the product of the normal allele from functioning in a heterozygous organism). Dominant negative effects are seen particularly in the case of genes whose products function as aggregates (dimers and multimers).

In contrast, gain of function is likely when only specific changes cause a given disease phenotype. Gains of truly novel functions are not common except in cancer, but in inherited diseases, gain of function usually means that the mutant gene is expressed at the wrong time in development, in the wrong tissue, in response to wrong signals, or at an inappropriately high level. The spectrum of gain-of-function mutations would therefore be more restricted, and deletion or disruption of the gene would not produce the disease.

Genetic Effects of Radiation

Exposure of cells and organisms to ionizing radiation causes DNA damage. The cellular processing of radiation-induced damage to DNA by enzymes may result in a return to normal sequence and structure (Lobrich and others 1995), or processing may fail or may cause alterations in DNA that lead to lethality or heritable changes (mutations and chromosomal aberrations) in surviving cells. Heritable changes induced in reproductive (germ) cells can be transmitted to the following generations and cause genetic disease of one kind or another (a concept that lies at the core of estimation of the genetic risks posed by radiation). Changes induced in nonreproductive (somatic) cells have a small but finite probability of contributing to the complex process of carcinogenesis.

The types of mutational changes induced by radiation are broadly similar to the types that occur naturally, but the proportions of the different types are not the same. The results of molecular studies of radiation-induced germ cell mutations in experimental organisms and in mammalian somatic cells support the view that most radiation-induced mutations involve changes in large segments of the DNA, such as deletions that often encompass more than one gene. Hence, radiation readily induces the kinds of molecular changes that can derange a genome and lead to cancer. Conversely, many of those changes, if they occur in germ cells, are incompatible with embryo development and result in developmental abnormalities or lethal mutations in the germline, which would result in nonviable progeny.



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