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[[Archivo:Frameshift mutation.jpg|350px|thumb|Diferentes tipos de mutaciones de marco de lectura.]]
Una '''mutación con cambio, desplazamiento o desfase del marco de lectura''' (también conocida como '''error de marco''' o '''cambio de marco''') es un tipo de [[mutación genética|mutación]] causada por la [[inserción]] o [[deleción]] de un número de [[nucleótido]]s que no es múltiplo de tres en una secuencia de ADN. Debido a la naturaleza ternaria del [[código genético]] comprendido como una sucesión de [[codón|codones]]; la inserción o deleción de un número de nucleótidos no divisible por tres, puede cambiar el [[marco de lectura]] del gen, provocando una [[traducción (genética)|traducción]] completamente diferente a la original. Cuanto antes aparezca la inserción o deleción en el gen, mayor es la alteración que sufre la proteína.<ref name="isbn0-8053-9592-X">{{cite book |author=Losick, Richard; Watson, James D.; Tania A. Baker; Bell, Stephen; Gann, Alexander; Levine, Michael W. |title=Molecular biology of the gene |publisher=Pearson/Benjamin Cummings |location=San Francisco |year=2008 |pages= |isbn=0-8053-9592-X |oclc= |doi= |accessdate=}}</ref>


Una mutación de marco de lectura no es lo mismo que un [[polimorfismo de nucleótido simple]], en el cual se produce el reemplazo de un único nucleótido, en lugar de ser perdido o ganado. Una mutación de desplazamiento de marco de lectura puede, por lo general, conducir a que la lectura de los codones en la secuencia posterior a la mutación codifique para aminoácidos diferentes. El desplazamiento de marco tamibién puede provocar la aparición o desaparición de un [[codón de terminación]] (''UAA'', ''UGA'', o ''UAG'') en una posición diferente de la secuencia. El polipéptido creado resulta entonces anormalmente corto o demasiado largo, y en la mayor parte de los casos; pierde su funcionalidad.
La '''mutación con cambio, desplazamiento o desfase del marco de lectura''' (''frameshift mutation'', en [[idioma inglés|inglés]]) es una [[mutación]] que inserta o borra un simple [[nucleótido]] en una secuencia de [[ADN]]. Debido a la naturaleza de la expresión genética, en forma de triplete, la inserción o borrado puede alterar la agrupación de [[codón|codones]], dando como resultado una traducción completamente diferente del original.


Las mutaciones de marco de lectura aparecen en varias enfermedades genéticas tales como la [[enfermedad de Tay-Sachs]] y [[fibrosis quística]]; aumentan la susceptibilidad a ciertos tipos de [[cáncer]] y a algunos tipos de [[hipercolesterolemia familiar]]. En 1997,<ref name="HIV resistance">{{cite journal|last = Zimmerman|first = PA|coauthors = Buckler-White, A; Alkhatib, G; Spalding, T; Kubofcik, J; Combadiere, C; Weissman, D; Cohen, O; Rubbert, A; Lam, G; Vaccarezza, M; Kennedy, PE; Kumaraswami, V; Giorgi, JV; Detels, R; Hunter, J; Chopek, M; Berger, EA; Fauci, AS; Nutman, TB; Murphy, PM|title = Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk.|journal = Molecular medicine (Cambridge, Mass.)|date = January 1997|volume = 3|issue = 1|pages = 23–36|pmid = 9132277|accessdate = 21 April 2013}}</ref> se consiguió establecer la relación entre una mutación de marco de lectura y la resistencia a la infección por el virus [[VIH]]. Se ha propuesto a las mutaciones con cambio de marco de lectura como una posible fuente de diversidad biológica, como en el conocido caso de la aparición de la [[nylonasa]]; sin embargo, esta interpretación todavía está sujeta a controversias. Un estudio de Negoro ''et al'' (2006)<ref>http://www.jbc.org/content/280/47/39644.full.pdf+html</ref> llegó a la conclusión de que esta mutación probablemente no fue un desplazamiento del marco de lectura, sino una sustitución de dos aminoácidos en la hendidura catalítica de una [[esterasa]] acestral que permitió amplificar su actividad hidrolítica.
En esencia, esto ocurre cuando se añade o elimina un número de nucleótidos que no es igual a tres en la secuencia genética. A partir del punto de mutación, la lectura del [[código genético]] resulta en sentido equivocado, dando como resultado la inserción de [[aminoácido]]s completamente diferentes en la secuencia de la [[proteína]] original.
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==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.

[[File:Cdmb.svg|250px|thumb|The [[central dogma]] model]]

===Central Dogma===

{{Main|Central dogma of molecular biology}}

In 1956 [[Francis Crick]] described the flow of genetic information from [[DNA]] to a specific amino acid arrangement for making a [[protein]] as the central dogma.<ref name="isbn0-8053-9592-X"/> For a cell to properly function, proteins are required to be produced accurately for structural and for [[catalytic]] activities. An incorrectly made protein can have determinental effects on [[Cell (biology)|cell]] viability and in most cases cause the higher [[organism]] to become unhealthy by abnormal cellular functions. To ensure that the [[genome]] successfully passes the information on, [[proofreading]] mechanisms such as exonucleases and [[mismatch repair]] systems are incorporated in [[DNA replication]] .<ref name="isbn0-8053-9592-X"/>

===Transcription and Translation===
{{Main|Transcription (genetics)|Translation (biology)}}
[[File:Translation-genetics.png|200px|thumb|The [[translation]] process]]
After DNA replication, the reading of a selected section of genetic information is accomplished by [[transcription (genetics)|transcription]].<ref name="isbn0-8053-9592-X"/>
Nucleotides containing the genetic information is now on a single strand messenger template called [[mRNA]]. The mRNA is incorporated with a subunit of the [[ribosome]] and interacts with an [[rRNA]]. 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]] are being joined together until a [[stop codon]] (UAG, UGA or UAA) is reached. At this point the [[polypeptide]] (protein) has been synthesised and is released.<ref name="isbn0-8053-9592-X"/> 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, [[Guanosine triphosphate|GTP]] hydrolysis activity of [[EF-Tu]] a form of kinetic stability, and a proofreading mechanism as EF-Tu is released.<ref name="isbn0-8053-9592-X"/>

Frameshifting may also occur during [[prophase]] translation, producing different proteins from overlapping open reading frames, such as the gag-pol-env [[retroviral]] proteins. This is fairly common in [[viruses]] and also occurs in [[bacteria]] and [[yeast]] (Farabaugh, 1996). [[Reverse transcriptase]], as opposed to [[RNA Polymerase II]], 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]] the error rate inducing frameshift mutations is only somewhere in the range of .0001 and .00001.<ref name="rna polymerase II">{{cite journal|last=Zhang|first=J|title=Host RNA polymerase II makes minimal contributions to retroviral frame-shift mutations.|journal=The Journal of general virology|date=August 2004|volume=85|issue=Pt 8|pages=2389–95|pmid=15269381|accessdate=21 March 2013|doi=10.1099/vir.0.80081-0}}</ref>

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]] 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]] can also be used to insert or delete Uridine into the mRNA after transcription, this allows for the correct reading frame.<ref>{{cite book|last=al.]|first=James D. Watson ... [et|title=Molecular biology of the gene|year=2007|publisher=Benjamin Cummings|location=San Francisco, Calif.|isbn=978-0-8053-9592-1|edition=6th ed.}}</ref>

===Codon-triplet importance===

{{Main|Genetic code}}

[[File:Rna-codons-protein.png|200px|thumb|The three letter code, the [[codon]]]]
A [[codon]] is a set of three [[nucleotides]], a triplet that code for a certain [[amino acid]]. The first codon establishes the reading frame, whereby a new codon begins. A proteins amino acid backbone [[sequence]] is defined by contiguous triplets.<ref name="isbn0-7167-7108-X">{{cite book |author=Cox, Michael; Nelson, David R.; Lehninger, Albert L |title=Lehninger principles of biochemistry |publisher=W.H. Freeman |location=San Francisco |year=2008 |pages= |isbn=0-7167-7108-X |oclc= |doi= |accessdate=}}</ref> 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.<ref name="isbn0-8053-9592-X"/>
[[File:Point Mutation.jpg|250px|thumb|Example of different types of point mutations]]
<!-- Deleted image removed: [[File:Frameshift mutations.jpg|250px|thumb|Example of amino acid changes in frameshift mutation]] -/->

==Mechanism==

Frameshift mutations can occur randomly or be caused by an external stimuli. 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===

{{Main|mutation}}

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 [[UV]]-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. [[E. coli]] pol I Kf and T7 DNA polymerase mutant [[enzymes]] devoid of 3′ → 5′ exonuclease activity produce UV-induced revertants at higher frequency than did their [[exonuclease]] proficient counterparts. The data indicatee that loss of proofreading activity increased the frequency of UV-induced frameshifts.<ref>{{cite journal|last=Sagher|first=Daphna|coauthors=Turkington, Edith; Acharya, Sonia; Strauss, Bernard|title=Production of UV-induced Frameshift Mutations in Vitro by DNA Polymerases Deficient in 3′ → 5′ Exonuclease Activity|journal=Journal of Molecular Biology|volume=240|issue=3|pages=226–242|doi=10.1006/jmbi.1994.1437}}</ref>

===Detection===

====Fluorescence====

The effects of neighboring bases and secondary structure to detect the frequency of frameshift mutations has been investigated in depth using [[fluorescence]]. Fluorescently tagged DNA, by means of base analogues, permits one to study the local changes of a DNA sequence.<ref>{{citation |first=Neil P. |last=Johnson |coauthors=Walter A. Baase, Peter H. von Hippel |title=Low-energy circular dichroism of 2-aminopurine dinucleotide as a probe of local conformation of DNA and RNA |quote=PNAS 2004 101:3426-3431; published online before print March 1, 2004 |doi=10.1073/pnas.0400591101}}</ref> 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.<ref>{{citation |first=Walter A. |last=Baase |coauthors=Davis Jose , Benjamin C. Ponedel , Peter H. von Hippel , and Neil P. Johnson |title=DNA models of trinucleotide frameshift deletions: the formation of loops and bulges at the primer–template junction |quote=Nucleic Acids Research Advance Access published on April 1, 2009 |doi=10.1093/nar/gkn1042 |periodical=Nucleic Acids Research |volume=37 |issue=5 |pages=1682–1689}}</ref>

====Sequencing====

Sanger [[sequencing]] and pyrosequencing 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 indels 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]].<ref name="predicting frameshifts" />

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]] 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.<ref name="TuckerMarra2009">{{cite journal|last1=Tucker|first1=Tracy|last2=Marra|first2=Marco|last3=Friedman|first3=Jan M.|title=Massively Parallel Sequencing: The Next Big Thing in Genetic Medicine|journal=The American Journal of Human Genetics|volume=85|issue=2|year=2009|pages=142–154|issn=00029297|doi=10.1016/j.ajhg.2009.06.022|pmid=19679224|pmc=2725244}}</ref> 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.<ref name="WalshCasadei2011">{{cite journal|last1 = Walsh|first1 = T.|last2 = Casadei|first2 = S.|last3 = Lee|first3 = M. K.|last4 = Pennil|first4 = C. C.|last5 = Nord|first5 = A. S.|last6 = Thornton|first6 = A. M.|last7 = Roeb|first7 = W.|last8 = Agnew|first8 = K. J.|last9 = Stray|first9 = S. M.|last10 = Wickramanayake|first10 = A.|last11 = Norquist|first11 = B.|last12 = Pennington|first12 = K. P.|last13 = Garcia|first13 = R. L.|last14 = King|first14 = M.-C.|last15 = Swisher|first15 = E. M.|title = From the Cover: Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing|journal = Proceedings of the National Academy of Sciences|volume = 108|issue = 44|year = 2011|pages = 18032–18037|issn = 0027-8424|doi = 10.1073/pnas.1115052108}}</ref> An experiment to determine the accuracy of this newer sequencing method tested for 21 genes and had no false positive calls for frameshift mutations.<ref name="WalshLee2010">{{cite journal|last1=Walsh|first1=T.|last2=Lee|first2=M. K.|last3=Casadei|first3=S.|last4=Thornton|first4=A. M.|last5=Stray|first5=S. M.|last6=Pennil|first6=C.|last7=Nord|first7=A. S.|last8=Mandell|first8=J. B.|last9=Swisher|first9=E. M.|last10=King|first10=M.-C.|title=Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing|journal=Proceedings of the National Academy of Sciences|volume=107|issue=28|year=2010|pages=12629–12633|issn=0027-8424|doi=10.1073/pnas.1007983107}}</ref>

====Diagnosis====

A US [[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]] and seqeuncing of the suspect gene. The amino acid sequence encoded by the gene is then predicted.<ref>US Patent [http://www.google.com/patents?vid=USPAT5958684 5,958,684] (September 28, 1999) "Diagnosis of Neurodegenerative Disease" by Leeuwen ''et al''</ref>

===Frequency===
Even though the cell has various ways to ensure the correct transfer of genetic information beginning at DNA replication, during translation and the rules that govern the genetic code. Mutations do occur and frameshift mutation is not the only type. There are also two other types of point mutations, namely a [[missense mutation]] and a [[nonsense mutation]].<ref name="isbn0-8053-9592-X"/> A frameshift mutation drastically changes the coding capacity of the message(genetic information).<ref name="isbn0-8053-9592-X"/> Small insertions or deletions (those less than 20 base pairs) make up 24% of mutations in disease.<ref name="predicting frameshifts">{{cite journal|last=Hu|first=J|coauthors=Ng, PC|title=Predicting the effects of frameshifting indels.|journal=Genome Biology|date=Feb 9, 2012|volume=13|issue=2|pages=R9|pmid=22322200|accessdate=20 March 2013|doi=10.1186/gb-2012-13-2-r9}}</ref>

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]].<ref name="editing frameshift mutation">{{cite journal|last=Harfe|first=BD|coauthors=Jinks-Robertson, S|title=Removal of frameshift intermediates by mismatch repair proteins in Saccharomyces cerevisiae.|journal=Molecular and Cellular Biology|date=July 1999|volume=19|issue=7|pages=4766–73|pmid=10373526|accessdate=20 March 2013}}</ref> [[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]] 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.<ref name="editing frameshift mutation" />

[[Huntington’s disease]] 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).<ref>{{cite journal|last=Davies|first=J E|coauthors=Rubinsztein, D C|title=Polyalanine and polyserine frameshift products in Huntington's disease|journal=Journal of Medical Genetics|volume=43|issue=11|pages=893–896|doi=10.1136/jmg.2006.044222}}</ref>

==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.
[[File:mutations on BRCA1.jpg|250px|thumb|Frequency of mutations on BRCA1 gene on chromosome 17]]
[[File:mutations on BRCA2.jpg|250px|thumb|Frequency of mutations on BRCA2 gene on chromosome 13]]

===Types===

====Cancer====

{{Main|cancer}}

Frameshift mutations are known to be a factor in [[colorectal]] cancer as well as other [[cancers]] with [[microsatellite instability]]. 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]], 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.<ref name="microsatellite instability">{{cite journal|last=Schmoldt|first=A|coauthors=Benthe, HF; Haberland, G|title=Digitoxin metabolism by rat [[liver]] microsomes.|journal=Biochemical pharmacology|date=Sep 1, 1975|volume=24|issue=17|pages=1639–41|doi=10.1093/hmg/ddq151|accessdate=20 March 2013}}</ref> In prostate cancer a frameshift mutation changes the [[open reading frame]] (ORF) and prevents [[apoptosis]] from occurring. This leads to an unregulated growth of the [[tumor]]. While there are environmental factors that contribute to the progression of [[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.<ref name="somatic mutations in prostate cancer">{{cite journal|last=Xu|first=XiaoLin|coauthors=Zhu, KaiChang; Liu, Feng; Wang, Yue; Shen, JianGuo; Jin, Jizhong; Wang, Zhong; Chen, Lin; Li, Jiadong; Xu, Min|title=Identification of somatic mutations in human prostate cancer by RNA-Seq|journal=Gene|doi=10.1016/j.gene.2013.01.046|accessdate=21 March 2013}}</ref> 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.<ref name="cancer genomics">{{cite web|title=Cancer Genomics|url=http://www.cancer.gov/cancertopics/understandingcancer/cancergenomics/AllPages|publisher=National Cancer Institute at the National Institute of Health|accessdate=24 March 2013}}</ref>

====Crohn's Disease====
[[Crohn's Disease]] has an association with the NOD2 gene. A frameshift mutation within the coding region of the gene can be a factor in Crohn's Disease. The mutation is an isertion of a [[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.<ref>{{cite journal|last=Ogura|first=Y|coauthors=Bonen, DK; Inohara, N; Nicolae, DL; Chen, FF; Ramos, R; Britton, H; Moran, T; Karaliuskas, R; Duerr, RH; Achkar, JP; Brant, SR; Bayless, TM; Kirschner, BS; Hanauer, SB; Nuñez, G; Cho, JH|title=A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.|journal=Nature|date=May 31, 2001|volume=411|issue=6837|pages=603–6|pmid=11385577|doi=10.1038/35079114}}</ref>

====Cystic Fibrosis====
[[Cystic Fibrosis]] (CF) is a disease based on mutations in the CF [[transmembrane]] conductance regulator (CFTR) gene. There are over 1500 mutations identified, but not all cause the disease.<ref name="guidelines for CF">{{cite journal|last=Farrell|first=Philip M.|coauthors=Rosenstein, Beryl J.; White, Terry B.; Accurso, Frank J.; Castellani, Carlo; Cutting, Garry R.; Durie, Peter R.; LeGrys, Vicky A.; Massie, John; Parad, Richard B.; Rock, Michael J.; Campbell, Preston W.|title=Guidelines for Diagnosis of Cystic Fibrosis in Newborns through Older Adults: Cystic Fibrosis Foundation Consensus Report|journal=The Journal of Pediatrics|volume=153|issue=2|pages=S4–S14|doi=10.1016/j.jpeds.2008.05.005|accessdate=21 March 2013}}</ref> 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]] and occur in about 1% of patients tested. These mutations were identified through Sanger sequencing.<ref name="frameshift mutations in CF">{{cite journal|last=Iannuzzi|first=MC|coauthors=Stern, RC; Collins, FS; Hon, CT; Hidaka, N; Strong, T; Becker, L; Drumm, ML; White, MB; Gerrard, B|title=Two frameshift mutations in the cystic fibrosis gene.|journal=American Journal of Human Genetics|date=February 1991|volume=48|issue=2|pages=227–31|pmid=1990834|accessdate=21 March 2013}}</ref>

====HIV====

{{Main|HIV/AIDS}}

[[CCR5]] 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 region that adds to the likelihood of the development of HIV. This region on the open reading frame [[Open reading frame|ORF]] 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.<ref name="HIV resistance"/>

====Tay-Sachs Disease====
[[Tay-Sachs Disease]] 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]] but symptoms do not appear until approximately 6 months of age. There is no cure for the disease.<ref name="tay sachs">{{cite web|title=Learning About Tay-Sachs Disease|url=http://www.genome.gov/10001220|publisher=National Human Genome Research Institute|accessdate=24 March 2013}}</ref> 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]] 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.<ref name="Tay-Sachs mutations">{{cite journal|last=Myerowitz|first=R|title=Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene.|journal=Human Mutation|year=1997|volume=9|issue=3|pages=195–208|pmid=9090523|accessdate=24 March 2013|doi=10.1002/(SICI)1098-1004(1997)9:3<195::AID-HUMU1>3.0.CO;2-7}}</ref>

====Smith-Magenis Syndrome====
[[Smith-Magenis syndrome]] (SMS)is a complex [[syndrome]] 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]] 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 [[Recombination hotspot|hotspot]] insertion/deletions (SNindels) and therefore a primary target for analysis in patients suspected for mutations in RAI1.<ref>{{cite journal|last=Truong|first=Hoa T|coauthors=Dudding, Tracy; Blanchard, Christopher L.; Elsea, Sarah H|title=Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature|journal=BMC Medical Genetics|volume=11|issue=1|page=142|doi=10.1186/1471-2350-11-142}}</ref>

====Hypertrophic Cardiomyopathy====
[[Hypertrophic cardiomyopathy]] is the most common cause of [[sudden cardiac death|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.<ref name="pmid21262074">{{cite journal |author=Chung WK, Kitner C, Maron BJ |title=Novel frameshift mutation in Troponin C ( TNNC1) associated with hypertrophic cardiomyopathy and sudden death |journal=Cardiol Young |volume=21 |issue=3 |pages=345–8 |date=June 2011 |pmid=21262074 |doi=10.1017/S1047951110001927 |url=}}</ref>

===Cures===
Finding a cure for the diseases caused by frameshift mutations are rare. Research into this is evident. One example is a primary [[immunodeficiency]] (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 fustion 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]]. 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 in tact. 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 [[Genetic recombination|recombination]], [[mitotic]] 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.<ref name="PID treatments">{{cite journal|last=Hu|first=Hailiang|coauthors=Gatti, Richard A|title=New approaches to treatment of primary immunodeficiencies: fixing mutations with chemicals|journal=Current Opinion in Allergy and Clinical Immunology|volume=8|issue=6|pages=540–546|doi=10.1097/ACI.0b013e328314b63b}}</ref>

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.<ref>European Patent [http://www.google.com/patents/EP1369126A1?cl=en] (December 10, 2003) "Use of coding microsatellite region frameshift mutation-derived peptides for treating cancer" by Bork ''et al''</ref>


{{Mutation}}

[[Category:Mutation]]
-->

==Véase también==
<!-- * [[Translational frameshift]] -->
* [[Mutación genética]]
* [[Transcripción (genética)]]
* [[Traducción (genética)]]
* [[codón]]
* [[proteína]]
* [[marco de lectura]]
* [[mutación puntual]]
* [[Enfermedad de Crohn]]
* [[Enfermedad de Tay-Sachs]]

==Referencias==
{{reflist|2}}

== Lecturas adicionales ==

* {{cite journal | author = Farabaugh PJ | title = Programmed translational frameshifting | journal = Annu. Rev. Genet. | volume = 30 | issue = 1| pages = 507–28 | year = 1996 | pmid = 8982463 | doi = 10.1146/annurev.genet.30.1.507 | url = | issn = }}
* {{cite book | author = Lewis, Ricki | authorlink = | editor = | others = | title = Human Genetics: Concepts and Applications | edition = 6th | language = | publisher = McGraw Hill | location = Boston, Mass | year = 2005 | origyear = | pages = 227–228 | quote = | isbn = 0-07-111156-5 | oclc = | doi = | url = | accessdate = }}
* {{citation |url=http://www.talkorigins.org/origins/postmonth/apr04.html |title=Nylonase Enzymes |accessdate=02-06-2009 |date=April 2004}}


==Enlaces externos==
* {{MeshName|Frameshift+Mutation}}
*[http://www.ncbi.nlm.nih.gov/projects/SNP/ NCBI dbSNP database] — "a central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms"
* [http://www.ebi.ac.uk/Tools/Wise2/index.htm Wise2] - aligns a [[protein]] against a DNA sequence allowing [[frameshift]]s and [[intron]]s
* [http://fasta.bioch.virginia.edu/fasta_www2/fasta_www.cgi?rm=select&pgm=fy FastY] - compare a DNA sequence to a protein sequence database, allowing gaps and [[frameshift]]s
* [http://bioinfo.lifl.fr/path/ Path] - tool that compares two [[frameshift]] proteins (back-[[Translation (genetics)|translation]] principle)
* [http://www.hgmd.cf.ac.uk/ac/index.php HGMD] - Human Genome Mutation Database


== Véase también ==
* [[Mutación]]


[[Categoría:Genética]]
[[Categoría:Genética]]

Revisión del 22:43 28 feb 2014

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Uso de esta plantilla: {{En desarrollo|nombre de usuario|t={{sust:CURRENTTIMESTAMP}}}} o {{sust:En desarrollo}}
Para otros usos de este término, véase Mutación (desambiguación).
Diferentes tipos de mutaciones de marco de lectura.

Una mutación con cambio, desplazamiento o desfase del marco de lectura (también conocida como error de marco o cambio de marco) es un tipo de mutación causada por la inserción o deleción de un número de nucleótidos que no es múltiplo de tres en una secuencia de ADN. Debido a la naturaleza ternaria del código genético comprendido como una sucesión de codones; la inserción o deleción de un número de nucleótidos no divisible por tres, puede cambiar el marco de lectura del gen, provocando una traducción completamente diferente a la original. Cuanto antes aparezca la inserción o deleción en el gen, mayor es la alteración que sufre la proteína.[1]​

Una mutación de marco de lectura no es lo mismo que un polimorfismo de nucleótido simple, en el cual se produce el reemplazo de un único nucleótido, en lugar de ser perdido o ganado. Una mutación de desplazamiento de marco de lectura puede, por lo general, conducir a que la lectura de los codones en la secuencia posterior a la mutación codifique para aminoácidos diferentes. El desplazamiento de marco tamibién puede provocar la aparición o desaparición de un codón de terminación (UAA, UGA, o UAG) en una posición diferente de la secuencia. El polipéptido creado resulta entonces anormalmente corto o demasiado largo, y en la mayor parte de los casos; pierde su funcionalidad.

Las mutaciones de marco de lectura aparecen en varias enfermedades genéticas tales como la enfermedad de Tay-Sachs y fibrosis quística; aumentan la susceptibilidad a ciertos tipos de cáncer y a algunos tipos de hipercolesterolemia familiar. En 1997,[2]​ se consiguió establecer la relación entre una mutación de marco de lectura y la resistencia a la infección por el virus VIH. Se ha propuesto a las mutaciones con cambio de marco de lectura como una posible fuente de diversidad biológica, como en el conocido caso de la aparición de la nylonasa; sin embargo, esta interpretación todavía está sujeta a controversias. Un estudio de Negoro et al (2006)[3]​ llegó a la conclusión de que esta mutación probablemente no fue un desplazamiento del marco de lectura, sino una sustitución de dos aminoácidos en la hendidura catalítica de una esterasa acestral que permitió amplificar su actividad hidrolítica.

Véase también

Referencias

  1. ↑ Losick, Richard; Watson, James D.; Tania A. Baker; Bell, Stephen; Gann, Alexander; Levine, Michael W. (2008). Molecular biology of the gene. San Francisco: Pearson/Benjamin Cummings. ISBN 0-8053-9592-X. 
  2. ↑ Zimmerman, PA; Buckler-White, A; Alkhatib, G; Spalding, T; Kubofcik, J; Combadiere, C; Weissman, D; Cohen, O; Rubbert, A; Lam, G; Vaccarezza, M; Kennedy, PE; Kumaraswami, V; Giorgi, JV; Detels, R; Hunter, J; Chopek, M; Berger, EA; Fauci, AS; Nutman, TB; Murphy, PM (January 1997). «Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk.». Molecular medicine (Cambridge, Mass.) 3 (1): 23-36. PMID 9132277. 
  3. ↑ http://www.jbc.org/content/280/47/39644.full.pdf+html

Lecturas adicionales


Enlaces externos

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