What Does Missense Mutation Mean?

• Almost 300,000 children are born with sickle-cell anemia every year in people of African origin.
• The famous Astrophysicist, Dr. Stephen Hawking has been suffering from ALS for more than 50 years and is only person to have survived this disease for so long.

Mutation can be described as a change in the sequence of the nucleotides that make the DNA. A mutation can occur in any cell of the body and may have certain effects depending on where the mutations may occur.

The change of the sequence of nucleotide can be of a small-scale―where only a small gene is affected―or it may be large-scale, where the chromosomal structure may be hampered.

Point mutations are small-scale mutations, where one nucleotide is substituted for another nucleotide. It usually occurs as a result of an error in DNA replication. Such mutation are classified as transitions or transversions.

In transitions, a purine is usually substituted for a purine, or a pyrimidine is substituted for a pyrimidine. In transversions, a pyrimidine is substituted for a purine, and vice-versa.

Missense mutation is a point mutation, where substitution of one nucleotide with another results into a codon that codes for a different amino acid.

Depending on the amino acid being substituted, the resulting protein may be rendered non-functional as the protein may lose its activity, or may result in incorrect folding of the protein and cause an alteration in the shape of the protein.

Missense mutation is different from nonsense mutation, where substitution of a nucleotide changes a codon to a stop codon and results in the premature release of the polypeptide.

Most of the time, a change in a nucleotide may result in a codon that codes for the same amino acid, thanks to the degeneracy of codons (multiple codons coding for the same amino acid) or for a similar amino acid resulting into a functional protein. Such a point mutation is usually termed as a silent mutation.

Missense mutation is responsible for a number of congenital disorders. We will now discuss a few examples of diseases caused by this mutation.

The red blood cells are observed to be sickle-shaped in many cases and may result in blood clots causing a stroke, severe attacks of pain, increased risk of infections, continuous destruction of red blood cells that may lead to anemia and elevated bilirubin.

Cause: Altered codon from GAG to GTG due transversion of 20^th nucleotide from A to T. As a result, glutamic acid on the seventh position is substituted for valine in the beta chain of hemoglobin.

Mutations in the genes coding for the enzyme superoxide dismutase 1 (SOD1) could lead to amyotrophic lateral sclerosis (ALS). This disorder involves the death of neurons in the brain that leads to loss of motor functions. It is characterized by stiff muscles, muscle twitching, and loss of muscle mass that may be lead to difficulty in breathing, swallowing, and breathing. Most individuals die from respiratory failure within three to five years of the onset of symptoms.

Cause: The 46^th codon coding for histidine is changed to arginine, rendering the SOD 1 enzyme inactive. This mutation causes death of the individual almost 15 years after the onset of symptoms.

The 4^th codon coding for alanine to valine due to a missense mutation. The course of this form of the disease is very rapid, and a person may survive only up to 1½ years after the onset of symptoms.

Progeria is an extremely rare disorder in which the sufferer displays signs of aging at a very young age. The earliest symptoms may include stunted growth, patches on the skin (as seen in case of scleroderma), full body hair loss, wrinkled skin, poor vision, kidney failure, and cardiac complications. However, normal motor and mental development is seen.

Mandibuloacral dysplasia is characterized by abnormal bone development and fat distribution accompanying skin pigmentation. Individuals with this disorder show stunted growth, underdeveloped collarbone and lower jaw, loss of bone from the fingertips, delayed closure of the skull and other deformities of the joint. Some also exhibit symptoms similar to that in progeria.

Cause: These disorders are caused by missense mutation in the LMNA gene. The nucleotide in the 1580th position on the DNA. This mutation causes the codon CGT to be changed to CTT. Thus, an arginine to be replaced by an leucine in the 527^th position.

In addition to these, missense mutation has also been linked to other disorders like congenital nephrotic syndrome and epidermolysis bullosa.