Mitochondrial+Disorders

=**Objectives**=


 * 1. Be able to describe how the unique properties of mitochondria (and the mitochondrial chromosome) influence the pattern of inheritance and expression of mitochondrial DNA mutations.** (p.615, 617-619)

__Unique Properties of Mitochondrial Genome__ Mitochondria containa cirlcular double-stranded chromosome (mtDNA). This mtDNA is transcribed and translated within the mitochondron and encodes genes for 13 polypeptides for electron transport chain proteins, 2 rRNAs, and 22 tRNAs. Ploidy of mtDNA is in a given cell is in the 1,000's with each mitochondrion containing 2-10 copies.

mtDNA uses a different genetic code comapred to nuclear genes. It encodes and uses its own 12S and 16S rRNA's. The mtDNA is transcribed and translated without introns and polycistronically, suggesting the bacterial origin of mitochondria. mtDNA has a very high mutation rate, allowing mitochondrial genome to change within a single generation by the accumulation of somatic mutations. mtDNA polymerase gamma is an nuclear encoded enzyme that is responsible for proof reading mtDNA.

Both wildtype and mutant mtDNA can co-exist within the same cell. __Homeoplasmy__ refers to cells with only one type of mtDNA while __Heteroplasmy__ refers to multiple types of mtDNA in a cell. Normal individuals will have 99.9% identical mtDNA; however, different tissues can contain different proportions of mutant and mtDNA. This is due to the fact that mtDNA replicates independently from nuclear DNA and because mitochondria segregate into daughter cells independently from nuclear chromosomes (replicative segregation). As a result, there is a threshold effect due to heteroplasmy where 95-90% of mutant mtDNA needs to be present in order for abnormal phenotype to be detectable.

Tissues differen on their dependence on oxidative phosphorylation and had different amounts of mitochondria. Heart, skeletal muscle, brain, CNS, liver, kidney, and insulin-forming islets of the pancreas most heavily rely on oxidative phosphorylation. As a result, these tissues will be most sensitive to clinical manifestations of mitochondrial disorders.

mtDNA encoded traits are transmitted __exclusively__ by the maternal line, for the most part. This is because the sperm have very few mitochondria of which none survive within the fertilized egg. On the other hand, oocytes contain as many as 100,000 mitochondria.


 * 2. Be able to recognize pedigrees showing a maternal (mitochondrial) pattern of inheritance. Students are expected to be able to correctly solve problems requiring such knowledge.** (p.616)

Mitochondrial inheritance is characterized by: (1) Transmissing solely by the mother to sons and daughters (2) Equal number of males and females affected (no gender bias in progeny) (3) Only females can transmit these traits (gender bias in transmission/uniparental transmission)