MUTATIONS

MUTATIONS As is well known, the term mutation refers to permanent changes in the DNA. Those that affect germ cells are transmitted to the progeny and may give rise to inherited diseases. Mutations in somatic cells are not transmitted to the progeny but are important in the causation of cancers and some congenital malformations.

Details of specific mutations and their effects are discussed along with the relevant disorders throughout this text. Here we cite only some common examples of gene mutations and their effects.

Point mutations result from the substitution of a single nucleotide base by a different base, resulting in the replacement of one amino acid by another in the protein product. The mutation giving rise to sickle cell anemia is an excellent example of a point mutation that alters the meaning of the genetic code. Such mutations are sometimes called missense mutations.

In contrast, certain point mutations may change an amino acid codon to a chain termination codon, or stop codon. Such "nonsense" mutations interrupt translation, and the resultant truncated proteins are rapidly degraded.

Frameshift mutations occur when the insertion or deletion of one or two base pairs alters the reading frame of the DNA strand.

Trinucleotide repeat mutations belong to a special category, because these mutations are characterized by amplification of a sequence of 3 nucleotides. Although the specific nucleotide sequence that undergoes amplification differs in various disorders, all affected sequences share the nucleotides guanine (G) and cytosine (C). For example, in fragile X syndrome, prototypical of this category of disorders, there are 200 to 4000 tandem repeats of the sequence CGG within a gene called FMR1. In normal populations, the number of repeats is small, averaging 29. The expansions of the trinucleotide sequences prevent normal expression of the FMR1 gene, thus giving rise to mental retardation. Another distinguishing feature of trinucleotide repeat mutations is that they are dynamic (i.e., the degree of amplification increases during gametogenesis). These features, discussed in greater detail later in this chapter, influence the pattern of inheritance and the phenotypic manifestations of the diseases caused by this class of mutations.

To these well-known categories, it is necessary to add a heterogeneous group of genetic disorders that, like mendelian disorders, involve single genes but do not follow simple mendelian rules of inheritance. These single-gene disorders with nonclassic inheritance include those resulting from triplet repeat mutations, those arising from mutations in mitochondrial DNA, and those in which the transmission is influenced by an epigenetic phenomenon called genomic imprinting.

With this brief review of the nature of mutations, we can turn our attention to the three major categories of genetic disorders: (1) those related to mutant genes of large effect, (2) diseases with multifactorial (polygenic) inheritance, and (3) those arising from chromosomal aberrations. The first category, sometimes referred to as mendelian disorders, includes many uncommon conditions, such as the storage diseases and inborn errors of metabolism, all resulting from single-gene mutations of large effect. Most of these conditions are hereditary and familial. The second category includes some of the most common disorders of humans, such as hypertension and diabetes mellitus. Multifactorial, or polygenic, inheritance implies that both genetic and environmental influences condition the expression of a phenotypic characteristic or disease. The third category includes disorders that are the consequence of numeric or structural abnormalities in the chromosomes.