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A frameshift mutation (also called a framing error or a reading frame shift) is a
genetic mutation Image:Darwin Hybrid Tulip Mutation 2014-05-01.jpg, A tulip flower exhibiting a partially yellow petal due to a mutation in its genes In biology, a mutation is an alteration in the base sequence, nucleotide sequence of the genome of an organism, ...
caused by
indel Indel is a molecular biology term for an insertion or deletion of bases in the genome of an organism. It is classified among small genetic variations, measuring from 1 to 10 000 base pairs in length, including insertion and deletion events that ...
s ( insertions or deletions) of a number of
nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotide
s in a DNA sequence that is not divisible by three. Due to the triplet nature of
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...

gene expression
by
codon The genetic code is the set of rules used by living cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or reli ...

codon
s, the insertion or deletion can change the
reading frame In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, mechani ...

reading frame
(the grouping of the codons), resulting in a completely different
translation Translation is the communication of the meaning Meaning most commonly refers to: * Meaning (linguistics), meaning which is communicated through the use of language * Meaning (philosophy), definition, elements, and types of meaning discusse ...
from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein. A frameshift mutation is not the same as a
single-nucleotide polymorphism In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interacti ...
in which a nucleotide is replaced, rather than inserted or deleted. A
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during Translation (biology), translation that results in the production of multiple, unique proteins from a single ...
mutation will in general cause the reading of the codons after the mutation to code for different amino acids. The frameshift mutation will also alter the first stop codon ("UAA", "UGA" or "UAG") encountered in the sequence. The polypeptide being created could be abnormally short or abnormally long, and will most likely not be functional. Frameshift mutations are apparent in severe genetic diseases such as
Tay–Sachs disease Tay–Sachs disease is a genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene In biology, a gene (from ''genos'' "...Wilhelm Johannse ...
; they increase susceptibility to certain cancers and classes of familial hypercholesterolaemia; in 1997, a frameshift mutation was linked to resistance to infection by the HIV retrovirus. Frameshift mutations have been proposed as a source of biological novelty, as with the alleged creation of
nylonase
nylonase
, however, this interpretation is controversial. A study by Negoro ''et al'' (2006) found that a frameshift mutation was unlikely to have been the cause and that rather a two amino acid substitution in the
active site
active site
of an ancestral
esterase An esterase is a hydrolase Hydrolase is a class of enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemist ...
resulted in nylonase.


Background

The information contained in DNA determines protein function in the cells of all organisms. Transcription and translation allow this information to be communicated into making proteins. However, an error in reading this communication can cause protein function to be incorrect and eventually cause disease even as the cell incorporates a variety of corrective measures.


Central dogma

In 1956
Francis Crick Francis Harry Compton Crick (8 June 1916 – 28 July 2004) was a British molecular biologist, biophysicist, and neuroscientist A neuroscientist (or neurobiologist) is a scientist A scientist is a person who conducts Scientific method, scie ...

Francis Crick
described the flow of genetic information from
DNA Deoxyribonucleic acid (; DNA) is a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the set of physical ...

DNA
to a specific amino acid arrangement for making a
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
as the central dogma. For a cell to properly function, proteins are required to be produced accurately for structural and for
catalytic that utilizes a low-temperature oxidation catalyst to convert carbon monoxide to less toxic carbon dioxide Carbon dioxide (chemical formula ) is a colorless gas with a density about 53% higher than that of dry air. Carbon dioxide molecules ...
activities. An incorrectly made protein can have detrimental effects on cell viability and in most cases cause the higher
organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological ...

organism
to become unhealthy by abnormal cellular functions. To ensure that the
genome In the fields of molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, M ...

genome
successfully passes the information on,
proofreading Proofreading is the reading Reading is the process of taking in the sense or meaning of letters, symbols, ''etc.'', especially by sight or touch. For educators and researchers, reading is a multifaceted process involving such areas as wor ...
mechanisms such as
exonuclease Exonucleases are enzymes Enzymes () are protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir ...
s and
mismatch repair DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of base Base or BASE may refer to: Brands and enterprises * Base (mobile telephony provider), a Belgian mobile telecommuni ...
systems are incorporated in
DNA replication In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, mo ...

DNA replication
.


Transcription and translation

After DNA replication, the reading of a selected section of genetic information is accomplished by transcription. Nucleotides containing the genetic information are now on a single strand messenger template called
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA i ...

mRNA
. The mRNA is incorporated with a subunit of the
ribosome Ribosomes ( ), also called Palade granules, are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (mRNA translation). Ribosomes link amino acids ...

ribosome
and interacts with an
rRNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA A non-coding RNA (ncRNA) is an RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance or material consis ...
. The genetic information carried in the codons of the mRNA are now read (decoded) by anticodons of the tRNA. As each codon (triplet) is read,
amino acids Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acids
are being joined together until a
stop codon Stop may refer to: Places *Stop, Kentucky Stop is an unincorporated area, unincorporated community located in Wayne County, Kentucky, United States. The origin of the name "Stop" is obscure. References Unincorporated communities in Wa ...
(UAG, UGA or UAA) is reached. At this point the
polypeptide Peptides (from Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ), refers collectively to the dialects of the Greek language spoken ...
(protein) has been synthesised and is released. For every 1000 amino acid incorporated into the protein, no more than one is incorrect. This fidelity of codon recognition, maintaining the importance of the proper reading frame, is accomplished by proper base pairing at the ribosome A site, GTP hydrolysis activity of
EF-Tu EF-Tu (elongation factor thermo unstable) is a Prokaryotic elongation factors, prokaryotic elongation factor responsible for catalyzing the binding of an aminoacyl-tRNA (aa-tRNA) to the ribosome. It is a G protein, G-protein, and facilitates th ...
a form of kinetic stability, and a proofreading mechanism as EF-Tu is released. Frameshifting may also occur during
prophase Prophase () is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the Cell (biology), cell enters prophase. The main occurrences in prophase are the condensation of the ...

prophase
translation, producing different proteins from overlapping open reading frames, such as the gag-pol-env
retroviral A retrovirus is a type of virus A virus is a submicroscopic infectious agent that Viral replication, replicates only inside the living Cell (biology), cells of an organism. Viruses infect all types of life forms, from animals and plant ...
proteins. This is fairly common in
viruses A virus is a wikt:submicroscopic, submicroscopic infectious agent that Viral replication, replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, incl ...
and also occurs in
bacteria Bacteria (; common noun bacteria, singular bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typ ...

bacteria
and
yeast Yeasts are eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular ...

yeast
(Farabaugh, 1996).
Reverse transcriptase A reverse transcriptase (RT) is an enzyme Enzymes () are protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providing and , an ...
, as opposed to
RNA Polymerase II RNA polymerase II (RNAP II and Pol II) is a multiprotein complex is a protein complex functioning as a molecular biological machine A molecular machine, nanite, or nanomachine is a molecular component that produces quasi-mechanical movements (o ...
, is thought to be a stronger cause of the occurrence of frameshift mutations. In experiments only 3–13% of all frameshift mutations occurred because of RNA Polymerase II. In
prokaryotes A prokaryote () is a single-celled organism A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contig ...

prokaryotes
the error rate inducing frameshift mutations is only somewhere in the range of .0001 and .00001. There are several biological processes that help to prevent frameshift mutations. Reverse mutations occur which change the mutated sequence back to the original
wild type The wild type (WT) is the phenotype In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proce ...
sequence. Another possibility for mutation correction is the use of a suppressor mutation. This offsets the effect of the original mutation by creating a secondary mutation, shifting the sequence to allow for the correct amino acids to be read.
Guide RNA Guide RNA (gRNA) is a piece of RNAs that function as guides for RNA- or DNA-targeting Enzyme, enzymes, which they form Protein–ligand complex, complexes with. Very often these enzymes will delete, insert or otherwise alter the targeted RNA or ...
can also be used to insert or delete Uridine into the mRNA after transcription, this allows for the correct reading frame.


Codon-triplet importance

A
codon The genetic code is the set of rules used by living cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or reli ...

codon
is a set of three
nucleotides Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotides
, a triplet that code for a certain
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
. The first codon establishes the reading frame, whereby a new codon begins. A protein's amino acid backbone
sequence In mathematics Mathematics (from Greek: ) includes the study of such topics as numbers (arithmetic and number theory), formulas and related structures (algebra), shapes and spaces in which they are contained (geometry), and quantities and t ...

sequence
is defined by contiguous triplets. Codons are key to translation of genetic information for the synthesis of proteins. The reading frame is set when translating the mRNA begins and is maintained as it reads one triplet to the next. The reading of the genetic code is subject to three rules the monitor codons in mRNA. First, codons are read in a 5' to 3' direction. Second, codons are nonoverlapping and the message has no gaps. The last rule, as stated above, that the message is translated in a fixed reading frame.


Mechanism

Frameshift mutations can occur randomly or be caused by an external stimulus. The detection of frameshift mutations can occur via several different methods. Frameshifts are just one type of mutation that can lead to incomplete or incorrect proteins, but they account for a significant percentage of errors in DNA.


Genetic or environmental

This is a genetic mutation at the level of nucleotide bases. Why and how frameshift mutations occur are continually being sought after. An environmental study, specifically the production of -induced frameshift mutations by DNA polymerases deficient in 3′ → 5′ exonuclease activity was done. The normal sequence 5′ GTC GTT TTA CAA 3′ was changed to GTC GTT T TTA CAA (MIDT) of GTC GTT C TTA CAA (MIDC) to study frameshifts. pol I Kf and T7 DNA polymerase mutant
enzymes Enzymes () are protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958 ...
devoid of 3′ → 5′ exonuclease activity produce UV-induced revertants at higher frequency than did their
exonuclease Exonucleases are enzymes Enzymes () are protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir ...
proficient counterparts. The data indicates that loss of proofreading activity increases the frequency of UV-induced frameshifts.


Detection


Fluorescence

The effects of neighboring bases and secondary structure to detect the frequency of frameshift mutations has been investigated in depth using
fluorescence Fluorescence is the emission of light Light or visible light is electromagnetic radiation within the portion of the electromagnetic spectrum that is visual perception, perceived by the human eye. Visible light is usually defined as ha ...

fluorescence
. Fluorescently tagged DNA, by means of base analogues, permits one to study the local changes of a DNA sequence. Studies on the effects of the length of the primer strand reveal that an equilibrium mixture of four hybridization conformations was observed when template bases looped-out as a bulge, i.e. a structure flanked on both sides by duplex DNA. In contrast, a double-loop structure with an unusual unstacked DNA conformation at its downstream edge was observed when the extruded bases were positioned at the primer–template junction, showing that misalignments can be modified by neighboring DNA secondary structure.


Sequencing

Sanger sequencing Sanger sequencing is a method of DNA sequencing based on the selective incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication. After first being developed by Frederick Sanger and colleagues in 1977, i ...
and
pyrosequencingPyrosequencing is a method of DNA sequencing (determining the order of nucleotides Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers deoxyribonucleic acid (D ...
are two methods that have been used to detect frameshift mutations, however, it is likely that data generated will not be of the highest quality. Even still, 1.96 million
indel Indel is a molecular biology term for an insertion or deletion of bases in the genome of an organism. It is classified among small genetic variations, measuring from 1 to 10 000 base pairs in length, including insertion and deletion events that ...
s have been identified through Sanger sequencing that do not overlap with other databases. When a frameshift mutation is observed it is compared against the Human Genome Mutation Database (HGMD) to determine if the mutation has a damaging effect. This is done by looking at four features. First, the ratio between the affected and conserved DNA, second the location of the mutation relative to the transcript, third the ratio of conserved and affected amino acids and finally the distance of the indel to the end of the
exon An exon is any part of a gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance#History, Mendelian units of heredity..." (Greek language, Greek) meaning ''generation'' or ...
. Massively Parallel Sequencing is a newer method that can be used to detect mutations. Using this method, up to 17 gigabases can be sequenced at once, as opposed to limited ranges for
Sanger sequencing Sanger sequencing is a method of DNA sequencing based on the selective incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication. After first being developed by Frederick Sanger and colleagues in 1977, i ...
of only about 1 kilobase. Several technologies are available to perform this test and it is being looked at to be used in clinical applications. When testing for different carcinomas, current methods only allow for looking at one gene at a time. Massively Parallel Sequencing can test for a variety of cancer causing mutations at once as opposed to several specific tests. An experiment to determine the accuracy of this newer sequencing method tested for 21 genes and had no false positive calls for frameshift mutations.


Diagnosis

A US
patent A patent is a type of intellectual property Intellectual property (IP) is a category of property Property is a system of rights that gives people legal control of valuable things, and also refers to the valuable things themselves. Depe ...

patent
(5,958,684) in 1999 by Leeuwen, details the methods and reagents for diagnosis of diseases caused by or associated with a gene having a somatic mutation giving rise to a frameshift mutation. The methods include providing a tissue or fluid sample and conducting gene analysis for frameshift mutation or a protein from this type of mutation. The nucleotide sequence of the suspected gene is provided from published gene sequences or from
cloning Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction Asexual reproduction is a type ...

cloning
and sequencing of the suspect gene. The amino acid sequence encoded by the gene is then predicted.


Frequency

Despite the rules that govern the genetic code and the various mechanisms present in a cell to ensure the correct transfer of genetic information during the process of DNA replication as well as during translation, mutations do occur; frameshift mutation is not the only type. There are at least two other types of recognized point mutations, specifically
missense mutation In genetics Genetics is a branch of biology concerned with the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) Though heredity had been observed for millennia, Gregor Mendel, Moravia, Moravian scientist an ...
and
nonsense mutation Nonsense is a communication Communication (from Latin ''communicare'', meaning "to share") is the act of developing Semantics, meaning among Subject (philosophy), entities or Organization, groups through the use of sufficiently mutually under ...
. A frameshift mutation can drastically change the coding capacity (genetic information) of the message. Small insertions or deletions (those less than 20 base pairs) make up 24% of mutations that manifest in currently recognized genetic disease. Frameshift mutations are found to be more common in repeat regions of DNA. A reason for this is because of slipping of the polymerase enzyme in repeat regions, allowing for mutations to enter the
sequence In mathematics Mathematics (from Greek: ) includes the study of such topics as numbers (arithmetic and number theory), formulas and related structures (algebra), shapes and spaces in which they are contained (geometry), and quantities and t ...

sequence
.
Experiment An experiment is a procedure carried out to support or refute a hypothesis, or determine the efficacy or likelihood of something previously untried. Experiments provide insight into Causality, cause-and-effect by demonstrating what outcome oc ...

Experiment
s can be run to determine the frequency of the frameshift mutation by adding or removing a pre-set number of nucleotides. Experiments have been run by adding four basepairs, called the +4 experiments, but a team from
Emory University Emory University is a private Private or privates may refer to: Music * "In Private "In Private" was the third single in a row to be a charting success for United Kingdom, British singer Dusty Springfield, after an absence of nearly two dec ...
looked at the difference in frequency of the mutation by both adding and deleting a base pair. It was shown that there was no difference in the frequency between the addition and deletion of a base pair. There is however, a difference in the end result of the protein.
Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A gener ...
is one of the nine codon reiteration disorders caused by polyglutamine expansion mutations that include spino-cerebellar ataxia (SCA) 1, 2, 6, 7 and 3, spinobulbar muscular atrophy and dentatorubal-pallidoluysianatrophy. There may be a link between diseases caused by polyglutamine and polyalanine expansion mutations, as frame shifting of the original SCA3 gene product encoding CAG/polyglutamines to GCA/polyalanines. Ribosomal slippage during translation of the SCA3 protein has been proposed as the mechanism resulting in shifting from the polyglutamine to the polyalanine-encoding frame. A dinucleotide deletion or single nucleotide insertion within the polyglutamine tract of huntingtin exon 1 would shift the CAG, polyglutamineen coding frame by +1 (+1 frame shift) to the GCA, polyalanine-encoding frame and introduce a novel epitope to the C terminus of Htt exon 1 (APAAAPAATRPGCG).


Diseases

Several diseases have frameshift mutations as at least part of the cause. Knowing prevalent mutations can also aid in the diagnosis of the disease. Currently there are attempts to use frameshift mutations beneficially in the treatment of diseases, changing the reading frame of the amino acids.


Cancer

Frameshift mutations are known to be a factor in
colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in vertebrates. Water is absorbed here and the remaining waste material is stored as feces before being removed by defec ...
cancer as well as other
cancers 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 tumor A benign tumor is a mass of cells Cell most often refers to: * Cell (biolog ...
with
microsatellite instability showing tumor-infiltrating lymphocytes in a case of colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large ...
. As stated previously, frameshift mutations are more likely to occur in a region of repeat sequence. When DNA mismatch repair does not fix the addition or deletion of bases, these mutations are more likely to be pathogenic. This may be in part because the tumor is not told to stop growing. Experiments in yeast and bacteria help to show characteristics of microsatellites that may contribute to defective DNA mismatch repair. These include the length of the
microsatellite A microsatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from one to six or more base pairs) are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome ...
, the makeup of the genetic material and how pure the repeats are. Based on experimental results longer microsatellites have a higher rate of frameshift mutations. The flanking DNA can also contribute to frameshift mutations. In prostate cancer a frameshift mutation changes the
open reading frame In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, mech ...

open reading frame
(ORF) and prevents
apoptosis Apoptosis (from Ancient Greek Ancient Greek includes the forms of the Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ) ...

apoptosis
from occurring. This leads to an unregulated growth of the
tumor A neoplasm () is a type of abnormal and excessive growth of tissue Tissue may refer to: Biology * Tissue (biology), an ensemble of similar cells that together carry out a specific function * ''Triphosa haesitata'', a species of geometer moth ...

tumor
. While there are environmental factors that contribute to the progression of
prostate cancer Prostate cancer is 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 tumor A benign tumor is a mass of cells Cell most o ...

prostate cancer
, there is also a genetic component. During testing of coding regions to identify mutations, 116 genetic variants were discovered, including 61 frameshift mutations. There are over 500 mutations on chromosome 17 that seem to play a role in the development of breast and ovarian cancer in the BRCA1 gene, many of which are frameshift.


Crohn's disease

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension, ...

Crohn's disease
has an association with the NOD2 gene. The mutation is an insertion of a
Cytosine Cytosine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical ...

Cytosine
at position 3020. This leads to a premature stop codon, shortening the protein that is supposed to be transcribed. When the protein is able to form normally, it responds to bacterial liposaccharides, where the 3020insC mutation prevents the protein from being responsive.


Cystic fibrosis

Cystic fibrosis Cystic fibrosis (CF) is a genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene In biology, a gene (from ''genos'' "...Wilhelm Johan ...
(CF) is a disease based on mutations in the CF
transmembrane A transmembrane protein (TP) is a type of integral membrane protein An integral membrane protein (IMP) is a type of membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane prot ...

transmembrane
conductance regulator (CFTR) gene. There are over 1500 mutations identified, but not all cause the disease. Most cases of cystic fibrosis are a result of the ∆F508 mutation, which deletes the entire amino acid. Two frameshift mutations are of interest in diagnosing CF, CF1213delT and CF1154-insTC. Both of these mutations commonly occur in tandem with at least one other mutation. They both lead to a small decrease in the function of the
lungs The lungs are the primary organs of the respiratory system The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animal ...

lungs
and occur in about 1% of patients tested. These mutations were identified through Sanger sequencing.


HIV

CCR5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array o ...
is one of the cell entry co-factors associated with HIV, most frequently involved with nonsyncytium-inducing strains, is most apparent in HIV patients as opposed to AIDS patients. A 32 base pair deletion in CCR5 has been identified as a mutation that negates the likelihood of an HIV infection. This region on the open reading frame contains a frameshift mutation leading to a premature stop codon. This leads to the loss of the HIV-coreceptor function in vitro. CCR5-1 is considered the wild type and CCR5-2 is considered to be the mutant allele. Those with a heterozygous mutation for the CCR5 were less susceptible to the development of HIV. In a study, despite high exposure to the HIV virus, there was no one homozygous for the CCR5 mutation that tested positive for HIV.


Tay–Sachs disease

Tay–Sachs disease Tay–Sachs disease is a genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene In biology, a gene (from ''genos'' "...Wilhelm Johannse ...
is a fatal disease affecting the central nervous system. It is most frequently found in infants and small children. Disease progression begins in the
womb The uterus (from Latin "uterus", plural ''uteri'') or womb () is the main female hormone-responsive, sex organ, secondary sex organ of the reproductive system in humans and most other mammals. Things occurring in the uterus are described with th ...
but symptoms do not appear until approximately 6 months of age. There is no cure for the disease. Mutations in the β-hexosaminidase A (Hex A) gene are known to affect the onset of Tay-Sachs, with 78 mutations of different types being described, 67 of which are known to cause disease. Most of the mutations observed (65/78) are single base substitutions or SNPs, 11 deletions, 1 large and 10 small, and 2 insertions. 8 of the observed mutations are frameshift, 6 deletions and 2 insertions. A 4 base pair insertion in exon 11 is observed in 80% of Tay-Sachs disease presence in the
Ashkenazi Ashkenazi Jews ( are a Jews, Jewish Jewish diaspora, diaspora population who Coalescent theory, coalesced in the Holy Roman Empire around the end of the first millennium. The traditional diaspora language of Ashkenazi Jews is Yiddish (a Ger ...
Jewish population. The frameshift mutations lead to an early stop codon which is known to play a role in the disease in infants. Delayed onset disease appears to be caused by 4 different mutations, one being a 3 base pair deletion.


Smith–Magenis syndrome

Smith–Magenis syndrome (SMS) is a complex
syndrome A syndrome is a set of medical signs and symptoms Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, rais ...
involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. The majority of SMS cases harbor an ~3.5 Mb common deletion that encompasses the retinoic acid induced-1 (RAI1) gene. Other cases illustrate variability in the SMS
phenotype In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular inter ...

phenotype
not previously shown for RAI1 mutation, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of a heptamericC-tract (CCCCCCC) in exon 3 resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. The results indicate that this heptameric C-tract is a preferential
recombination hotspotRecombination hotspots are regions in a genome that exhibit elevated rates of Homologous recombination, recombination relative to a neutral expectation. The recombination rate within hotspots can be hundreds of times that of the surrounding region. R ...
insertion/deletions (SNindels) and therefore a primary target for analysis in patients suspected for mutations in RAI1.


Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM) is a condition in which the heart becomes hypertrophy, thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ventricles. This results in the hea ...
is the most common cause of sudden death in young people, including trained athletes, and is caused by mutations in genes encoding proteins of the cardiac sarcomere. Mutations in the Troponin C gene (TNNC1) are a rare genetic cause of hypertrophic cardiomyopathy. A recent study has indicated that a frameshift mutation (c.363dupG or p.Gln122AlafsX30) in Troponin C was the cause of hypertrophic cardiomyopathy (and sudden cardiac death) in a 19-year-old male.


Cures

Finding a cure for the diseases caused by frameshift mutations is rare. Research into this is ongoing. One example is a primary
immunodeficiency Immunodeficiency, also known as immunocompromisation, is a state in which the immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ὀργα ...
(PID), an inherited condition which can lead to an increase in infections. There are 120 genes and 150 mutations that play a role in primary immunodeficiencies. The standard treatment is currently gene therapy, but this is a highly risky treatment and can often lead to other diseases, such as leukemia. Gene therapy procedures include modifying the zinc fringer nuclease fusion protein, cleaving both ends of the mutation, which in turn removes it from the sequence. Antisense-oligonucleotide mediated exon skipping is another possibility for Duchenne
muscular dystrophy Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular disease A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron A motor neuron (or motoneuron) is a n ...
. This process allows for passing over the mutation so that the rest of the sequence remains in frame and the function of the protein stays intact. This, however, does not cure the disease, just treats symptoms, and is only practical in structural proteins or other repetitive genes. A third form of repair is revertant mosaicism, which is naturally occurring by creating a reverse mutation or a mutation at a second site that corrects the reading frame. This reversion may happen by intragenic recombination,
mitotic In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In gene ...
gene conversion, second site DNA slipping or site-specific reversion. This is possible in several diseases, such as X-linked severe combined immunodeficiency (SCID), Wiskott–Aldrich syndrome, and Bloom syndrome. There are no drugs or other pharmacogenomic methods that help with PIDs. A European patent (EP1369126A1) in 2003 by Bork records a method used for prevention of cancers and for the curative treatment of cancers and precancers such as DNA-mismatch repair deficient (MMR) sporadic tumours and HNPCC associated tumours. The idea is to use immunotherapy with combinatorial mixtures of tumour-specific frameshift mutation-derived peptides to elicit a cytotoxic T-cell response specifically directed against tumour cells.European Paten

(December 10, 2003) "Use of coding microsatellite region frameshift mutation-derived peptides for treating cancer" by Bork ''et al''


See also

*
Translational frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during Translation (biology), translation that results in the production of multiple, unique proteins from a single ...
*
Mutation In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechan ...
*
Transcription (genetics) Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast a ...
*
Translation (biology) In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biolog ...

Translation (biology)
*
codon The genetic code is the set of rules used by living cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or reli ...

codon
*
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
*
reading frame In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, mechani ...

reading frame
*
point mutation A point mutation or substitution is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product ...

point mutation
*
Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension, ...

Crohn's disease
*
Tay–Sachs disease Tay–Sachs disease is a genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene In biology, a gene (from ''genos'' "...Wilhelm Johannse ...


References


Further reading

* * *


External links

*
NCBI dbSNP database
— "a central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms"

- aligns a
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
against a DNA sequence allowing
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during Translation (biology), translation that results in the production of multiple, unique proteins from a single ...
s and
intron An intron (for ''intragenic region'') is any Nucleic acid sequence, nucleotide sequence within a gene that is removed by RNA splicing during Post-transcriptional modification, maturation of the final RNA product. In other words, introns are non-c ...

intron
s
FastY
- compare a DNA sequence to a protein sequence database, allowing gaps and
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during Translation (biology), translation that results in the production of multiple, unique proteins from a single ...
s
Path
- tool that compares two
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during Translation (biology), translation that results in the production of multiple, unique proteins from a single ...
proteins (back-
translation Translation is the communication of the meaning Meaning most commonly refers to: * Meaning (linguistics), meaning which is communicated through the use of language * Meaning (philosophy), definition, elements, and types of meaning discusse ...
principle)
HGMD
- Human Genome Mutation Database {{Mutation Mutation