Medical Genetics 07 线粒体疾病的遗传 Inheritance of Mitochondrail Diseases

Medical 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.

Medical Genetics Mitochondria are extremely small (from 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 release the energy required for cellular functions.

Medical Genetics

A cell may have hundreds or even thousands of mitochondria depending on the particular cell ’ s need for energy. (For example, the average human liver cell contains more than a thousand mitochondria.)

Medical Genetics 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.

Medical Genetics

Unlike nuclear genes, which are inherited 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 first human disease that was associated with a mutation in mitochondrial DNA is called Leber's Hereditary Optic Neuropathy, or LHON.

Medical Genetics Intense SDH staining of a muscle fiber with mitochondrial proliferation mtDNA Point mutations Cardiomyopath y Leber's optic neuropathy Leigh's syndrome MELAS MERRF NARP/MILS Single deletion or duplication Ataxia, Leukodystrophy Diabetes: Maternal inheritance Kearns-Sayre Pearson's PEO: Sporadic Multiple deletions Aging Myositis Inclusion body COX- muscle fibers MNGIE PEO Wolfram Depletion of mtDNA Infantile myopathy Fatal "Later-onset" AZT treatment Several types of mtDNA defect Deafness Diabetes External ophthalmoplegia (PEO) Sporadic Maternal Dominant Recessive Leigh's Myopathy Rhabdomyolysis Sensory neuropathy Systemic disorders

Medical Genetics 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).

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.

Medical Genetics Mitochondrial circular DNA is shown.

Medical Genetics 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

Medical Genetics Mitochondria also have their own ribosomes and tRNA: 22 tRNAs rRNAs 16S, 12S, 5S

Medical Genetics 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.

Medical Genetics

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.

Medical Genetics 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.

Medical 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 Genetics Inheritance 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 affected offspring differ between different mtDNA mutations

Medical Genetics 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

Medical Genetics 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

Medical Genetics Mutation effects Often cause deficient function in respiratory-chain Abnormal Oxidative-phosphorylation enzymes

Medical Genetics Mutation distribution Homoplasmic: Similar distribution of mtDNA mutation in all tissues Heteroplasmic: Variable distribution of mtDNA mutation in different cells or tissues

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 Genetics Skewed heteroplasmy –mtDNA mutation surpasses pathogenic threshold in 1 tissue –Examples: A3243G may produce only cardiomyopathy; Myopathy with early respiratory involvement

Medical Genetics