1、Medical GeneticsMedical Genetics The normal 46 chromosomes in our body are contained in the center of the cell,which is called the nucleus.Mitochondria are structures in the cell located outside of the nucleus in the cytoplasm,that also contain genes that are separate from the ones in the nucleus.Me
2、dical Genetics Mitochondria are extremely small(from.002-.008 millimeters in length)rice-shaped structures whose details can only be seen with the electron microscope.Medical Genetics Mitochondria are often called the“powerhouses”of the cell because they are the site where sugar is broken down to re
3、lease the energy required for cellular functions.Medical GeneticsMedical Genetics A cell may have hundreds or even thousands of mitochondria depending on the particular cells need for energy.(For example,the average human liver cell contains more than a thousand mitochondria.)Medical Genetics In add
4、ition to containing the many proteins needed to control the energy release process,the mitochondria also contain a small amount of DNA that is used to direct the manufacture of thirteen of the proteins needed for its activities.Medical GeneticsMedical Genetics Unlike nuclear genes,which are inherite
5、d from both parents,mitochondrial genes are inherited only from the mother.Medical Genetics If there is a mutation in a mitochondrial gene,it is passed from a mother to all of her children;sons will not pass it on,but daughters will pass it on to all of their children,and so on.Medical Genetics The
6、first human disease that was associated with a mutation in mitochondrial DNA is called Lebers Hereditary Optic Neuropathy,or LHON.Medical Genetics Intense SDH stainingof a muscle fiber withmitochondrial proliferation mtDNA Point mutationsCardiomyopathyLebers optic neuropathyLeighs syndromeMELASMERRF
7、NARP/MILSSingle deletion or duplicationAtaxia,LeukodystrophyDiabetes:Maternal inheritance Kearns-SayrePearsonsPEO:SporadicMultiple deletionsAgingMyositisInclusion bodyCOX-muscle fibersMNGIEPEOWolframDepletion of mtDNA Infantile myopathy Fatal Later-onsetAZT treatmentSeveral types of mtDNA defectDeaf
8、nessDiabetesExternal ophthalmoplegia(PEO)Sporadic Maternal Dominant RecessiveLeighsMyopathyRhabdomyolysisSensory neuropathySystemic disordersMedical Genetics Mitochondria have some of their own DNA,ribosomes,and can make many of their own proteins.The DNA is circular and lies in the matrix.in puncta
9、te structures called nucleoids.Each nucleoid may contain 4-5 copies of the mitochondrial DNA(mtDNA).Medical Genetics To visualize the structure of mtDNA,the DNA was extracted and floated on a water surface.Then,it can be picked up by a plastic coated grid,and examined in the electron microscope.Medi
10、cal Genetics Mitochondrial circular DNA is shown.Medical GeneticsHuman mtDNA is 16,569 bp;encodes a number of mitochondrial proteins Subunits 1,2,and 3 of cytochrome oxidase Subunits 6,8 of the Fo ATPase Apocytochrome b subunit of CoQH2-Cytochrome C reductase Seven NADH-CoQ reductase subunits Medica
11、l GeneticsMitochondria also have their own ribosomes and tRNA:22 tRNAs rRNAs16S,12S,5S Medical GeneticsBoth strands of mammalian mtDNA are synthesized continuously as leading strands.Synthesis of the first mtDNA strand proceeds partially,pauses,and is then completed upon receipt of appropriate signa
12、ls.The result is that most mtDNA has D-loops.Synthesis of the second strand is initiated after the fork synthesizing the first strand passes the origin of second strand synthesis.During plastid DNA replication RNA primers are incompletely excised and replaced.As a result the plastid genome is a chim
13、eric DNA-RNA molecule.Origins of plastid DNA replication have been identified.Two D-loops are found in plastid DNA.They represent initiation on opposite DNA strands.Medical GeneticsMedical Genetics In mammals,99.99%of mitochondrial DNA(mtDNA)is inherited from the mother.This is because the sperm car
14、ries its mitochondria around a portion of its tail and has only about 100 mitochondria compared to 100,000 in the oocyte.Medical Genetics As the cells develop,more and more of the mtDNA from males is diluted out.Hence less than one part in 104 or 0.01%of the mtDNA is paternal.Medical GeneticsMedical
15、 Genetics This means that mutations of mtDNA can be passed from mother to child.It also has implications if one does cloning of mammals with the use of somatic cells.The nuclear DNA would be from the donor cell,but the mtDNA would be from the host cell.This is how Dolly the sheep was cloned.Medical
16、GeneticsInheritance During fertilization mtDNA is derived only from the oocyte;Maternal inheritance:mtDNA mutations transmitted only from mother;Mutations transmitted to all offspring,Male&Female;Increased Mutant mtDNA in the mothers blood increased Frequency of affected offspring Risks of having af
17、fected offspring differ between different mtDNA mutations Medical GeneticsThreshold effect%of mutant mtDNAs must be above a threshold to produce clinical manifestations%of mutant mtDNAs needed to cause cell dysfunction varies according to tissue oxidative requirements Disease signs especially manife
18、st in Tissues with a high energy expenditure:Dependent on oxidative metabolism Specific tissues:Brain,Heart&Muscle Medical GeneticsMitotic segregation%of mutant mtDNAs in daughter cells can shift at cell division Produces rapid changes of genotype that may lead to crossing of threshold Medical Genet
19、icsMutation effects Often cause deficient function in respiratory-chain Abnormal Oxidative-phosphorylation enzymes Medical GeneticsMutation distribution Homoplasmic:Similar distribution of mtDNA mutation in all tissues Heteroplasmic:Variable distribution of mtDNA mutation in different cells or tissu
20、es Medical Genetics The following diagram shows a family in which the mother passed the mutation to her three children,but only the daughters passed it to subsequent generations.Medical GeneticsSkewed heteroplasmy mtDNA mutation surpasses pathogenic threshold in 1 tissue Examples:A3243G may produce only cardiomyopathy;Myopathy with early respiratory involvement Medical GeneticsMedical Genetics
