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Missense mutation
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== Notable Examples == === LMNA === [[File:LMNA_protein_(1IFR)_mutation_R527L_PMID_22549407.png|thumb|375px|upright=1.3|Wild type (left) and mutated (right) form of lamin A (pdb id: 1IFR). Normally, Arginine 527 (blue) forms [[Salt bridge (protein)|salt bridge]] with glutamate 537 (magenta), but R527L substitution results in breaking this interaction (leucine has a nonpolar tail and therefore cannot form a static salt bridge).]] DNA: 5' - AAC AGC CTG <span style="background-color:#ccf">CGT</span> ACG GCT CTC - 3' 3' - TTG TCG GAC <span style="background-color:#ccf">GCA</span> TGC CGA GAG - 5' mRNA: 5' - AAC AGC CUG CGU ACG GCU CUC - 3' Protein: [[Asparagine|Asn]] [[Serine|Ser]] [[Leucine|Leu]] [[Arginine|Arg]] [[Threonine|Thr]] [[Alanine|Ala]] [[Leucine|Leu]] [[LMNA]] missense mutation (c.1580G>T) introduced at LMNA gene – position 1580 (nt) in the DNA sequence (CGT) causing the [[guanine]] to be replaced with the [[thymine]], yielding CTT in the DNA sequence. This results at the protein level in the replacement of the [[arginine]] by the [[leucine]] at the position 527.<ref>{{cite journal |vauthors=Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki JM, Yahia S, Abdel-Hadi D, Shams A, Ahmad N, Hamed S, Puzianowska-Kuznicka M |date=November 2012 |title=A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome |journal=European Journal of Human Genetics |volume=20 |issue=11 |pages=1134–1140 |doi=10.1038/ejhg.2012.77 |pmc=3476705 |pmid=22549407}}</ref> This leads to destruction of [[Salt bridge (protein)|salt bridge]] and structure destabilization. At [[phenotype]] level this manifests with overlapping [[mandibuloacral dysplasia]] and [[progeria syndrome]]. The resulting transcript and protein product is: DNA: 5' - AAC AGC CTG <span style="background-color:#ccf">CTT</span> ACG GCT CTC - 3' 3' - TTG TCG GAC <span style="background-color:#ccf">GAA</span> TGC CGA GAG - 5' mRNA: 5' - AAC AGC CUG CUU ACG GCU CUC - 3' Protein: [[Asparagine|Asn]] [[Serine|Ser]] [[Leucine|Leu]] [[Leucine|Leu]] [[Threonine|Thr]] [[Alanine|Ala]] [[Leucine|Leu]] === Rett Syndrome === Missense mutations in the MeCP2 protein can cause [[Rett syndrome]], otherwise known as the RTT phenotype.<ref name="Brown_2016">{{cite journal |vauthors=Brown K, Selfridge J, Lagger S, Connelly J, De Sousa D, Kerr A, Webb S, Guy J, Merusi C, Koerner MV, Bird A |date=February 2016 |title=The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome |journal=Human Molecular Genetics |volume=25 |issue=3 |pages=558–570 |doi=10.1093/hmg/ddv496 |pmc=4731022 |pmid=26647311}}</ref> This phenotype primarily effects females, as males do not live with this mutation past infancy.<ref name="Brown_2016" /> T158M, R306C and R133C are the most common missense mutations causing RTT.<ref name="Brown_2016" /> T158M is a mutation of an [[adenine]] being substituted for a [[guanine]] causing the [[threonine]] at amino acid position 158 being substituted with a [[methionine]].<ref>{{cite book |title=Comprehensive Guide to Autism |vauthors=Zhou Z, Goffin D |date=2014 |publisher=Springer New York |isbn=978-1-4614-4787-0 |veditors=Patel VB, Preedy VR, Martin CR |place=New York, NY |pages=2723–2739 |language=en |chapter=Modeling Rett Syndrome with MeCP2 T158A Knockin Mice |doi=10.1007/978-1-4614-4788-7_181 |access-date=2025-02-07 |chapter-url=https://link.springer.com/10.1007/978-1-4614-4788-7_181}}</ref> R133C is a mutation of a [[cytosine]] at base position 417 in the gene encoding the [[MECP2|MeCP2]] protein being substituted for a [[thymine]], causing an amino acid substitution at position 133 in the protein of [[arginine]] with [[cysteine]].<ref name=":8">{{cite journal |vauthors=Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY |date=October 1999 |title=Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 |journal=Nature Genetics |volume=23 |issue=2 |pages=185–188 |doi=10.1038/13810 |pmid=10508514}}</ref> === Sickle Cell === [[File:Sickle cell anemia.jpg|thumb|(1) Normal red blood cells and (2) sickled-cell red blood cells]][[Sickle cell disease|Sickle-cell disease]] changes the shape of red blood cells from round to sickle shaped.<ref name=":9">{{Cite journal |last1=Esoh |first1=Kevin |last2=Wonkam |first2=Ambroise |date=2021-03-01 |title=Evolutionary history of sickle-cell mutation: implications for global genetic medicine |url=https://academic.oup.com/hmg/article/30/R1/R119/6103809 |journal=Human Molecular Genetics |volume=30 |issue=R1 |pages=R119–R128 |doi=10.1093/hmg/ddab004 |issn=0964-6906 |pmc=8117455 |pmid=33461216}}</ref> In the most common variant of sickle-cell disease, the 20th nucleotide of the gene for the [[beta chain]] of [[hemoglobin]] is altered from the [[codon]] GAG to GTG.<ref name=":9" /> Thus, the 6th amino acid, [[glutamic acid]], is substituted by [[valine]]—notated as an "E6V" or a "Glu6Val" mutation—which causes the protein to be sufficiently altered with a sickle-cell phenotype.<ref>{{cite web |title=141900 Hemoglobin—Beta Locus; HBB: .0243 Hemoglobin S. Sickle Cell Anemia, included. Malaria, Resistance to, included. HBB, GLU6VAL — 141900.0243 |url=http://omim.org/entry/141900#141900Variants0243 |publisher=[[Mendelian Inheritance in Man|Online 'Mendelian Inheritance in Man']] (OMIM)}}</ref> The affected cells cause issues in the bloodstream as they can become sticky due to their improper ion transport leading to them being susceptible to water loss.<ref name=":1">{{Cite journal |last1=Parker |first1=J. C. |last2=Orringer |first2=E. P. |date=1990-04-27 |title=Sickle Cell Disease. Charles F. Whrrren and John F. Bertles, Eds. New York Academy of Sciences, New York, 1989. xiv, 477 pp., illus. $119. Annals of the New York Academy of Sciences, vol. 565. From a conference, Bethesda, MD, April 1988 |url=https://doi.org/10.1126/science.248.4954.502 |journal=Science |volume=248 |issue=4954 |pages=502 |doi=10.1126/science.248.4954.502 |pmid=17815604 |issn=0036-8075|url-access=subscription }}</ref> This can cause a buildup of blood cells that obstructs blood flow to any organ in the body.<ref name=":1" /> === Other conditions that can be caused by missense mutations === * [[Alzheimer's disease|Alzheimers]]<ref name=":0" /> * [[X-linked intellectual disability]]<ref name=":0" /> * [[Hypocholesterolemia]]<ref name=":0" /> * [[Tangier disease]]<ref name=":0" /> * Congenital [[nemaline myopathy]]<ref>{{Cite journal |last1=Yang |first1=Liu |last2=Yu |first2=Ping |last3=Chen |first3=Xiang |last4=Cai |first4=Tao |date=August 2016 |title=The de novo missense mutation N117S in skeletal muscle α-actin 1 causes a mild form of congenital nemaline myopathy |url=https://www.spandidos-publications.com/10.3892/mmr.2016.5429 |journal=Molecular Medicine Reports |language=en |volume=14 |issue=2 |pages=1693–1696 |doi=10.3892/mmr.2016.5429 |issn=1791-2997 |pmid=27357517}}</ref>
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