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1、Molecular basis of diseaseChapter 1111.1 Abormalities in genes and proteins are the molecular basis of diseases11.111.1 Abnormal gene and protein expression cause Diseases Abnormal gene and protein expression cause Diseases 11.1.1 Diseases caused by changes in gene structure11.1.2 Post-translational
2、 processing and transportation obstacles and diseases11.1.3 Diseases caused by abnormal protein degradationFragile X syndromeFragile X syndrome11.1.1.Diseases caused by changes in gene structureFragile X syndrome“CCG”repeats in the 5untranslated region of FMR1(fragile X mental retardation gene 1),an
3、d the copynumber is unstable.854 copies(normal person)55200 copies(Carrier)2001000 copies(patient)Myotonic dystrophy is caused by an excessive increase in CTG copynumber in the 3 untranslated region Friedreich ataxia is caused by excessive increase in intron CAA copynumber Huntingtons disease is cau
4、sed by excessive CAG copy number in thecoding areaThe increase in the number of tandem repeat copies is unstable,and it can expand with the passage of generations,so it is called dynamic mutation.Multiple types of genetic mutations1.Point mutation2.Missing3.Insert4.Inversion5.Dynamic mutationTypes o
5、f gene mutation1.Point mutation:For a single base change,at a certain position inthe primary structure of the gene,one base isreplaced by another.Divided into:transitiontransversionTypes of gene mutation2.Deletion:One single nucleotide or a nucleotide sequence is lost3.Insertion:The increase of one
6、or more nucleotides4.InversionThedirectionofaDNA sequenceinsidethechromosome is reversed.Types of gene mutation(1)Genetic effects of structural gene mutationsGenetic effects caused by gene mutations1.missense mutation2.nonsense mutation3.synonymous mutation4.frame-shift mutation hemoglobinopathyHemo
7、globin is composed of4 peptide chains(two alphaand two beta chains).Eachpeptide chain binds a heme.13Albinism11.1.2 Post-translational processing and transportation obstacles and diseasesTyrosinase and type generalized albinismPoint mutation of tyrosinase catalytic domainPoint mutations outside the
8、catalytic domain oftyrosinaseTyrosinase and type generalized albinismPoint mutations in the catalytic domain oftyrosinase can reduce or even eliminate theactivity of tyrosinase,and melanin synthesis isreduced or cannot be synthesized,resulting in type generalized albinism;Point mutations outside the
9、 catalytic domain oftyrosinase can also lead to loss of pigment and theprotein cannot be folded correctly.Tyrosinase withoutnormalfoldingcannotbeexportedfromtheendoplasmic reticulum and stay in the endoplasmicreticulum,which cannot complete its maturation andtransportation.Abnormal protein transport
10、TyrosinaseP proteinGolgi apparatusMelanomaP protein gene mutationMelanin synthesis disorder causes type generalized albinismERTyrosinase and type generalized albinismPost-translational processing and transportation obstacles and diseasesIn the bodys cells,genetic information is expressed in proteins
11、.Fornewly synthesized proteins to have complete biological activity,post-translational processing is required.Among them,obstacles inany part of the processing process will cause protein dysfunctioncause disease.The cause of type generalized albinism is that it occurs duringprotein post-translationa
12、l processing and transportation.Alzheimers disease:inhibition of proteasome activityAlzheimer s disease(AD)is a degenerative disease of the central nervous system.The first clinical manifestation is the recent decline in memory,followed by persistentintelligence decline,aphasia,loss of judgment and
13、reasoning ability,and movementdisorders.The most significant neuropathological histological features of AD are senileplaques,neurofibrillary tangles,and amyloid deposits on the blood vessel wall.It has been found that amyloid can affect the degradation of ubiquitin-dependentproteins by inhibiting 26
14、S proteasome activity.11.1.3 Diseases caused by abnormal protein degradationProtein degradation pathwayLysosomal pathway,degrading extracellular proteins engulfed by cellsUbiquitin-proteasome pathway,degrading intracellular ubiquitinated proteinsUbiquitin(ubiquitin,Ub)E1(specific ubiquitin activatin
15、g enzyme)E2(ubiquitin-binding enzyme),E3(ubiquitin ligase)ProteasomeProtein degradationDiseases caused by pathogenic microorganism genesInfection causes mechanical or biological damage；Fighting for nutrition causes nutritional deficiencies；Toxins cause abnormal cell metabolism；The integration of gen
16、es into the host genome causeschanges ingene structure and abnormal expression.Summary Through the study of the above knowledge,we have initiallylearned the molecular basis of the onset of certain diseases,whichare related to structural gene changes,post-translational processingand transportation obstacles and diseases and protein degradationabnormalities.Thank you!