In
genetics
Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar work ...
, a missense mutation is a
point mutation in which a single nucleotide change results in a
codon
The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
that codes for a different
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
. It is a type of
nonsynonymous substitution
A nonsynonymous substitution is a nucleotide mutation that alters the amino acid sequence of a protein. Nonsynonymous substitutions differ from synonymous substitutions, which do not alter amino acid sequences and are (sometimes) silent mutations. ...
.
Substitution of protein from DNA mutations
Missense mutation refers to a change in one amino acid in a protein, arising from a
point mutation in a single nucleotide. Missense mutation is a type of
nonsynonymous substitution
A nonsynonymous substitution is a nucleotide mutation that alters the amino acid sequence of a protein. Nonsynonymous substitutions differ from synonymous substitutions, which do not alter amino acid sequences and are (sometimes) silent mutations. ...
in a DNA sequence. Two other types of nonsynonymous substitution are the
nonsense mutations, in which a codon is changed to a premature
stop codon
In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in mess ...
that results in truncation of the resulting
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
, and the
nonstop mutations, in which a stop codon erasement results in a longer, nonfunctional protein.
Missense mutations can render the resulting protein nonfunctional, and such mutations are responsible for human diseases such as
Epidermolysis bullosa,
sickle-cell disease
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red ...
,
SOD1
Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fa ...
mediated
ALS
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
, and a substantial number of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s.
In the most common variant of sickle-cell disease, the 20th
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
of the gene for the
beta chain of
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythroc ...
is altered from the
codon
The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
GAG to GTG. Thus, the 6th amino acid
glutamic acid
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
is substituted by
valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...
—notated as an "E6V" mutation—and the protein is sufficiently altered to cause the sickle-cell disease.
Not all missense mutations lead to appreciable protein changes. An amino acid may be replaced by an amino acid of very similar chemical properties, in which case, the protein may still function normally; this is termed a neutral, "quiet", "silent" or conservative mutation. Alternatively, the amino acid substitution could occur in a region of the protein which does not significantly affect the protein secondary structure or function. When an amino acid may be encoded by more than one codon (so-called "degenerate coding") a mutation in a codon may not produce any change in translation; this would be a
synonymous substitution
A synonymous substitution (often called a ''silent'' substitution though they are not always silent) is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence i ...
and not a missense mutation.
Example
DNA: 5' - AAC AGC CTG
CGT ACG GCT CTC - 3'
3' - TTG TCG GAC
GCA TGC CGA GAG - 5'
mRNA: 5' - AAC AGC CUG CGU ACG GCU CUC - 3'
Protein:
Asn Ser Leu
Leu may refer to:
Businesses and organisations
* LEU, NYSE American stock symbol for Centrus Energy Corp.
* London Ecology Unit, a former body (1986-2000) which advised London boroughs on environmental matters
* Free and Equal (''LeU - Liberi e ...
Arg Thr Ala Leu
Leu may refer to:
Businesses and organisations
* LEU, NYSE American stock symbol for Centrus Energy Corp.
* London Ecology Unit, a former body (1986-2000) which advised London boroughs on environmental matters
* Free and Equal (''LeU - Liberi e ...
LMNA
Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins.
Function
In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, r ...
missense mutation (c.1580G>T) introduced at LMNA gene – position 1580 (nt) in the DNA sequence (CGT) causing the
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is ...
to be replaced with the
thymine
Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidin ...
, yielding CTT in the DNA sequence. This results at the protein level in the replacement of the
arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
by the
leucine
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- ...
at the position 527. This leads to destruction of
salt bridge and structure destabilization. At
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...
level this manifests with overlapping
mandibuloacral dysplasia
Mandibuloacral dysplasia (MAD) is a rare autosomal recessive syndrome characterized by mandibular hypoplasia, delayed cranial suture closure, dysplastic clavicles, abbreviated and club-shaped terminal phalanges, acroosteolysis, atrophy of the skin ...
and
progeria syndrome.
The resulting transcript and protein product is:
DNA: 5' - AAC AGC CTG
CTT ACG GCT CTC - 3'
3' - TTG TCG GAC
GAA TGC CGA GAG - 5'
mRNA: 5' - AAC AGC CUG CUU ACG GCU CUC - 3'
Protein:
Asn Ser Leu
Leu may refer to:
Businesses and organisations
* LEU, NYSE American stock symbol for Centrus Energy Corp.
* London Ecology Unit, a former body (1986-2000) which advised London boroughs on environmental matters
* Free and Equal (''LeU - Liberi e ...
Leu
Leu may refer to:
Businesses and organisations
* LEU, NYSE American stock symbol for Centrus Energy Corp.
* London Ecology Unit, a former body (1986-2000) which advised London boroughs on environmental matters
* Free and Equal (''LeU - Liberi e ...
Thr Ala Leu
Leu may refer to:
Businesses and organisations
* LEU, NYSE American stock symbol for Centrus Energy Corp.
* London Ecology Unit, a former body (1986-2000) which advised London boroughs on environmental matters
* Free and Equal (''LeU - Liberi e ...
Experimental analysis
Cancer associated missense mutations can lead to drastic destabilisation of the resulting protein. A method to screen for such changes was proposed in 2012, namely
fast parallel proteolysis (FASTpp)
Fast parallel proteolysis (FASTpp) is a method to determine the thermostability of proteins by measuring which fraction of protein resists rapid proteolytic digestion.
History and background
Proteolysis is widely used in biochemistry and cell ...
.
See also
*
Ka/Ks ratio
*
Missense mRNA
Missense mRNA is a messenger RNA bearing one or more mutated codons that yield polypeptides with an amino acid sequence different from the wild-type or naturally occurring polypeptide. Missense mRNA molecules are created when template DNA strands ...
References
External links
{{Mutation
Modification of genetic information
Mutation