Why does mutation cause genetic disorders

Anzilotti, MD. Larger text size Large text size Regular text size. What Is a Gene Mutation? What Are Genes? What Is DNA? What Is a Chromosome? What Causes a Gene Mutation? A gene can mutate because of: a change in one or more nucleotides of DNA a change in many genes loss of one or more genes rearrangement of genes or whole chromosomes Do Parents Pass Gene Mutations to Children?

Many human diseases have a genetic component. A genetic disorder is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence. Genetic disorders can be caused by a mutation in one gene monogenic disorder , by mutations in multiple genes multifactorial inheritance disorder , by a combination of gene mutations and environmental factors, or by damage to chromosomes changes in the number or structure of entire chromosomes, the structures that carry genes.

As we unlock the secrets of the human genome the complete set of human genes , we are learning that nearly all diseases have a genetic component. Some diseases are caused by mutations that are inherited from the parents and are present in an individual at birth, like sickle cell disease. Other diseases are caused by acquired mutations in a gene or group of genes that occur during a person's life.

Such mutations are not inherited from a parent, but occur either randomly or due to some environmental exposure such as cigarette smoke. In fact, some mutations can be beneficial. Over time, genetic mutations create genetic diversity, which keeps populations healthy. Many mutations have no effect at all.

These are called silent mutations. But the mutations we hear about most often are the ones that cause disease. Some well-known inherited genetic disorders include cystic fibrosis, sickle cell anemia, Tay-Sachs disease, phenylketonuria and color-blindness, among many others. All of these disorders are caused by the mutation of a single gene. Most inherited genetic diseases are recessive, which means that a person must inherit two copies of the mutated gene to inherit a disorder.

This is one reason that marriage between close relatives is discouraged; two genetically similar adults are more likely to give a child two copies of a defective gene.

Diseases caused by just one copy of a defective gene, such as Huntington's disease, are rare. These "hot spots" are often a result of the DNA sequence itself being more accessible to mutagens. Hot spots include areas of the genome with highly repetitive sequences, such as trinucleotide repeats, in which a sequence of three nucleotides is repeated many times. During DNA replication, these repeat regions are often altered because the polymerase can "slip" as it disassociates and reassociates with the DNA strand Viguera et al.

To better understand a polymerase slip, imagine you are reading a page of text that is a repeat of a simple sequence. Say that the whole page is just copies of the word "And" "And And And Now, imagine that while reading the page, you briefly glance away and then look back at the text. It's quite likely that you will have lost your place. As a result, you may read the wrong number of copies from the page.

Similarly, DNA polymerase sometimes slips and makes mistakes when reading repeats. Figure 3: Unequal crossing-over during meiosis. When homologous chromosomes misalign during meiosis, unequal crossing-over occurs. The result is the deletion of a DNA sequence in one chromosome, and the insertion of a DNA sequence in the other chromosome. Genetics: A Conceptual Approach, 2nd ed.

All rights reserved. In other cases, mutations alter the way a gene is read through either the insertion or the deletion of a single base. In these so-called frameshift mutations, entire proteins are altered as a result of the deletion or insertion. This occurs because nucleotides are read by ribosomes in groups of three, called codons.

Thus, if the number of bases removed or inserted from a gene is not a multiple of three, the reading frame for the rest of the protein is thrown off. To better understand this concept, consider the following sentence composed entirely of three-letter words, which provides an analogy for a series of three-letter codons:.

Now, say that a mutation eliminates the first G. As a result, the rest of the sentence is read incorrectly:. The same will happen in a protein. For example, a protein might have the following coding sequence:.

A codon translation table Figure 4 can be used to determine that this mRNA sequence would encode the following stretch of protein:. Now, suppose that a mutation removes the fourth nucleotide. The resulting code, separated into triplet codons, would read as follows:. Each of the STOP codons tells the ribosome to terminate protein synthesis at that point. Thus, the mutant protein is entirely different due to the deletion, and it's shorter due to the premature stop codon. Figure 4: The amino acids specified by each mRNA codon.

Multiple codons can code for the same amino acid. The codons are written 5' to 3', as they appear in the mRNA. As previously mentioned, DNA in any cell can be altered by way of a number of factors, including environmental influences, certain chemicals, spontaneous mutations, and errors that occur during the process of replication.

Each of these mechanisms is discussed in greater detail in the following sections. UV light can also cause covalent bonds to form between adjacent pyrimidine bases on a DNA strand, which results in the formation of pyrimidine dimers.

Repair machinery exists to cope with these mutations, but it is somewhat prone to error, which means that some dimers go unrepaired. Furthermore, some people have an inherited genetic disorder called xeroderma pigmentosum XP , which involves mutations in the genes that code for the proteins involved in repairing UV-light damage. In people with XP, exposure to UV light triggers a high frequency of mutations in skin cells, which in turn results in a high occurrence of skin cancer.

As a result, such individuals are unable to go outdoors during daylight hours. In addition to ultraviolet light, organisms are exposed to more energetic ionizing radiation in the form of cosmic rays, gamma rays, and X-rays.

Ionizing radiation induces double-stranded breaks in DNA, and the resulting repair can likewise introduce mutations if carried out imperfectly. Unlike UV light, however, these forms of radiation penetrate tissue well, so they can cause mutations anywhere in the body. Deamination , or the removal of an amine group from a base, may also occur. Deamination of cytosine converts it to uracil , which will pair with adenine instead of guanine at the next replication, resulting in a base substitution.

Repair enzymes can recognize uracil as not belonging in DNA, and they will normally repair such a lesion. However, if the cytosine residue in question is methylated a common modification involved in gene regulation , deamination will instead result in conversion to thymine.

Because thymine is a normal component of DNA, this change will go unrecognized by repair enzymes Figure 6. Figure 6: Deamination is a spontaneous mutation that occurs when an amine group is removed from a nitrogenous base. The nitrogenous base cytosine is converted to uracil after the loss of an amine group. Because uracil forms base-pairs with adenine, while cytosine forms base-pairs with guanine, the conversion of cytosine to uracil causes base substitutions in DNA.

Genetics: A Conceptual Approach , 2nd ed. Errors that occur during DNA replication play an important role in some mutations, especially trinucleotide repeat TNR expansions. It is thought that the ability of repeat sequences to form secondary structures, such as intrastrand hairpins, during replication might contribute to slippage of DNA polymerase, causing this enzyme to slide back and repeat replication of the previous segment Figure 7.

Supporting this hypothesis, lagging-strand synthesis has been shown to be particularly sensitive to repeat expansion. As previously mentioned, repeats also occur in nonmitotic tissue, and CAG repeats have further been shown to accumulate in mice defective for individual DNA repair pathways, suggesting that multiple repair mechanisms must be operative in repeat expansion in nonproliferating cells Pearson et al.

In agreement with this hypothesis, studies have revealed increased repeat instability following induction of double-stranded breaks and UV-induced lesions, which are corrected by nucleotide excision repair.

To date, all diseases associated with TNRs involve repeat instability upon transmission from parent to offspring, often in a sex-specific manner. For example, the CAG repeats that characterize Huntington's disease typically exhibit greater expansion when inherited paternally.

This expansion has been shown to occur prior to meiosis, when germ cells are proliferating.