医学遗传学-07线粒体疾病的遗传eng-v课件

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Medical Genetics,07,线粒体疾病的遗传,Inheritance of Mitochondrail Diseases,07线粒体疾病的遗传 Inheritance of Mi,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.,The normal 46 chromosom,Mitochondria are extremely small (from .002-.008 millimeters in length) rice-shaped structures whose details can only be seen with the electron microscope .,Mitochondria are extre,Mitochondria are often called the “powerhouses” of the cell because they are the site where sugar is broken down to release the energy required for cellular functions.,Mitochondria are ofte,医学遗传学-07线粒体疾病的遗传eng-v课件,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.),A cell may have hundre,In addition 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.,In addition to contain,医学遗传学-07线粒体疾病的遗传eng-v课件,Unlike nuclear genes, which are inherited from both parents, mitochondrial genes are inherited,only,from the mother.,Unlike nuclear genes,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.,If there is a mutatio,The first human disease that was associated with a mutation in mitochondrial DNA is called Lebers Hereditary Optic Neuropathy, or LHON.,The first human diseas,Intense SDH stainingof a muscle fiber withmitochondrial proliferation,mtDNA Point mutations,CardiomyopathyLebers optic neuropathyLeighs syndromeMELASMERRFNARP/MILS,Single deletion or duplication,Ataxia, LeukodystrophyDiabetes: Maternal inheritance Kearns-SayrePearsonsPEO: Sporadic,Multiple deletions,AgingMyositisInclusion bodyCOX- muscle fibersMNGIEPEOWolfram,Depletion of mtDNA,Infantile myopathy Fatal Later-onsetAZT treatment,Several types of mtDNA defect,DeafnessDiabetesExternal ophthalmoplegia (PEO) Sporadic Maternal Dominant RecessiveLeighsMyopathyRhabdomyolysisSensory neuropathySystemic disorders,1. Mitochondrial DNA,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 punctate structures called nucleoids. Each nucleoid may contain 4-5 copies of the mitochondrial DNA (mtDNA).,1. Mitochondrial DNA Mi,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.,To visualize the struc,Mitochondrial circular DNA is shown.,Mitochondrial circular D,Human 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,Human mtDNA is 16,569 bp; enco,Mitochondria also have their own ribosomes and tRNA:,22 tRNAs,rRNAs16S, 12S, 5S,Mitochondria also have their o,2. mtDNA replication,Both 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 signals. 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 chimeric 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.,2. mtDNA replicationBoth stran,医学遗传学-07线粒体疾病的遗传eng-v课件,3. Mitochondrial Inheritance,In mammals, 99.99% of mitochondrial DNA (mtDNA) is inherited from the mother. This is because the sperm carries its mitochondria around a portion of its tail and has only about 100 mitochondria compared to 100,000 in the oocyte.,3. Mitochondrial Inheritance,As the cells develop, more and more of the mtDNA from males is diluted out. Hence less than one part in 10,4,or 0.01% of the mtDNA is paternal.,As the cells develop,医学遗传学-07线粒体疾病的遗传eng-v课件,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.,This means that muta,Inheritance,During fertilization mtDNA is derived only from the oocyte;,Maternal inheritance: mtDNA mutations transmitted only from mother;,Mutations transmitted to all offspring, Male ,Increased Mutant mtDNA in the mothers blood increased Frequency of affected offspring,Risks of having affected offspring differ between different mtDNA mutations,Inheritance,Threshold 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 manifest in,Tissues with a high energy expenditure: Dependent on oxidative metabolism,Specific tissues: Brain, Heart & Muscle,Threshold effect,Mitotic segregation,% of mutant mtDNAs in daughter cells can shift at cell division,Produces rapid changes of genotype that may lead to crossing of threshold,Mitotic segregation,Mutation effects,Often cause deficient function in respiratory-chain,Abnormal Oxidative-phosphorylation enzymes,Mutation effects,Mutation distribution,Homoplasmic: Similar distribution of mtDNA mutation in all tissues,Heteroplasmic: Variable distribution of mtDNA mutation in different cells or tissues,Mutation distribution,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.,The following diagra,Skewed heteroplasmy,mtDNA mutation surpasses pathogenic threshold in 1 tissue,Examples: A3243G may produce only cardiomyopathy; Myopathy with early respiratory involvement,Skewed heteroplasmy,医学遗传学-07线粒体疾病的遗传eng-v课件,医学遗传学-07线粒体疾病的遗传eng-v课件,