Mitochondrial Inheritance

1. Mitochondrial Inheritance

2. Mitochondria is at a 0.5 µ width and 2-4 µ length. Structures of them are investigated in detail by electron microscopy. It consists of membrane and liquid (matrix) parts. It has a double membrane which consists of inner and outer membranes. There is a gap (40-80 Aº) between the inner and outer membranes. These membranes are different from each other.

3. Inmatrix, therearevariousenzymesthatareresponsiblefromproductionandfunctions of ribosoms, tRNAandmitochondrialgenes. • The whole proteins and RNA synthesized in nucleus, are not encoded by nucleer DNA. A small, but important part of them are encoded by mitochondrial genome.

4. 95% of theenergyforthecell is producedbymitochondria. • 5-10% of mitochondrialproteinsaresynthesizedbymitochondrial DNA. Because it has itsown DNA polymeraseand 3 types of RNA (tRNA, mRNA, rRNA).

5. Proteins synthesized in mitochondria can’t pass to cytosole, but some of the proteins synthesized in cytosole can pass to mitochondria. The mt genome consists of a circular and double strand DNA.One of the strands is the heavy chain (guanine rich) and the other is the light chain (cytosine rich)

6. The mitochondrial genome consists of a circular DNA of 16569bpand double stranded. Mitochondrial DNA (mtDNA) contains 37 genes (13 encode polypeptides, 2 rRNA, and 22 tRNAs). • Of these genes, 13 code for proteins of the oxidative phosphorylation complex. The other 22 tRNA’s and 2 rRNA’s are required for protein synthesis within the mitochondria.

7. 16.569bp equals to nearly 5523 codones. So, more than 90% of mitochondrial genome consists of coding regions (exon).

8. There are thousands of mitochondrial DNA (mtDNA) in every cell in which there is only two copies of nuclear DNA. • Mammals’ mtDNA is 1% of nuclear DNA. • mtDNA does not packaged by histone proteins.

9. Inheritance of Mitochondrial Mutations • Mitochondrial diseases have a distinct pattern of inheritance because of two unusual features:

10. mtDNA is replicated independently of the cell cycle and the individual copies are randomly distributed to the daughter cells during mitosis. • At cell division, the multiple copies of mtDNA in each of the mitochondria in a cell replicate and sort randomly among newly synthesized mitochondria. • The mitochondria, in turn, are distributed randomly between the two daughter cells.

11. Homoplasmy-Heteroplasmy • When a mutation arises in the mtDNA, it is at first present in only one of the mtDNA molecules in a mitochondrion. • However, a mitochondrion containing a mutant mtDNA will acquire multiple copies of the mutant molecule. • With cell division, a cell containing a mixture of normal and mutant mtDNAs can distribute to its daughter cells in very different proportions of mutant and wild-type mitochondrial DNA.

12. One daughter cell may, by chance, receive mitochondria that contain only a pure population of normal mtDNA or a pure population of mutant mtDNA (a situation known as homoplasmy). • Alternatively, the daughter cell may receive a mixture of mitochondria, some with and some without mutation (heteroplasmy). • Because the phenotypic expression of a mutation in mtDNA depends on the relative proportions of normal and mutant mtDNA in the cells making up different tissues, reduced penetrance and variable expressionare also typical features of mitochondrial disorders.

13. Homoplasmy and Heteroplasmy

14. Maternal Inheritance of mtDNA • The final mtDNA is inheritedmaternally. Sperm mitochondria are generally eliminated from the embryo, so that mtDNA is inherited from the mother. • Maternal inheritance in the presence of heteroplasmy in the mother is associated with additional features of mtDNA genetics that are of medical significance.

18. In heteroplasmy, there are 2 features of mtDNA: 1- One exception to maternal inheritance occurs when the mother is heteroplasmic for deletion mutation in her mtDNA; for unknown reasons, deleted mtDNA molecules are generally not transmitted from clinically affected mothers to their children. -mtDNA point mutations or duplications can be transmitted to the children from their mother.

19. 2- The number of mtDNA molecules in each of the oocytes are reduced before their amplification in the mature oocytes. • This restriction and subsequent amplification of mtDNA is during oogenesis. - So, mutated mtDNA percentage in the children of the mothers with mutated mtDNA molecules can differ from each other.

20. As might be expected, mothers with a high proportion of mutant mtDNA molecules are more likely to produce eggs with a higher proportion of mutant mtDNA and therefore are more likely to have clinically affected offspring than are mothers with a lower proportion.

23. Genetics of MitochondrialDiseases Themutation rate of mtDNA is nearly 100 timeshigherthanthemutation rate of nuclear DNA. Therearetworeasonswhythemitochondrialgenome is particularlyvulnerabletomutations. First, mitochondria is lack of DNA repairenzymesthatmaintain a lowcumulativemutationburden in thenucleargenome. Themitochondrialgenome,therefore, has mutationratesthatare 100 to 1000 timeshigherthanthe rate of mutations of thenucleargenome. Secondly, themtDNA is thepreferredtarget of freeradicals, becausetheydevelopduringtheoxidativephosphorilation in themitochondriathemselves. Theproximity of mtDNAtothesources of freeradicalsrendermtDNA far morevulnerableandmutablethannuclear DNA.

24. First pathogenic mutations reported - 1988 • Holt et al (1988) - large deletions in patients with mitochondrial myopathy • Wallace et al (1988) - point mutation in ND4 gene associated with Leber hereditary optic neuropathy (LHON) • The clinics of mitochondrial diseases are variable, but neuromuscular symptomes are mostly seen.

26. More than 100 rearrangements and 50 different point mutations are related with mtDNA diseases.

27. There are 3 types of mutations in mtDNA: 1- Missense mutations in genes of OXPHOS proteins 2- Point mutations of tRNA and rRNA genes, 3- Rearrangements causing deletions and duplications in mtDNA molecules.

28. Phenotype of Mitochondrial Diseases • Mitochondrial mutations usually affect tissues which need oxidative phosphorylation and high energy. • Different rearrangements and point mutations identified in mtDNA that can cause human disease, often involving the neuromuscular systems

29. Tissues are: • Central nervous system • Skeletal muscles • Heart • Pancreas • Eyes • Renal system

30. -myopathy, -ataxia, -retinopathy -optic neuropathy -hepatopathy, -kemik iliği yetmezliği, -diabetes mellitus, -migraine, -hearing loss,etc

31. Heteroplasmy causes some expressivity differences in mtDNA mutations. • For example, in the same family, some of the individuals can have DM and hearing loss, the others can have migraine or seizures.

32. Examples of mitochondrial diseases mtDNAdiseasesaremultifactorial. MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes • MERRF (Myoclonic Epilepsy with Ragged Red Fibres) • Leber Hereditary Optic Neuropathy (LHON) • External Ophthalmoplegia • Kearns-Sayre syndrome • Chronic progressive external ophthalmoplegia • NARP (Neurogenic weakness Ataxia with Retinitis Pigmentosa)

33. MELAS • An oftenly seen mtDNA mutation causes MELAS phenotype. (A3243G mutation in tRNALeu gene) • MELAS; • mitochondriyal encephalomyopathy, • lactic acidosis • Attacks like stroke

34. MELAS; causes diabetes and hearing loss in some families, and sometimes it can be with cardiomyopathy.

36. mtDNA diseases are multifactorial. • Kearns-Sayre and Pearson syndromes; • They occur sporadic in the families and there is no maternal inheritance, because in every patient there is a new mitochondrial mutation.

38. LHON (Leber’s Hereditary Optic Neuropathy) • An exception among the mitochondrial disorders is LHON. It is not a multisystem disorder, but only affects the optic nerve. Typical presentation is acute, painless loss of vision. Initially, it affects one eye, within weeks to months, it also affects the second eye. It progresses to severe optic atrophy. • For unknown reasons, males are more frequently affected. The age of onset is early adulthood, but may range from 8 to 60 years. Penetrance is low: 2/3 to ¾ of male and 90% of female mutation carriers remain asymptomatic throughout life.

39. Complications • Incomplete penetrance • Variable expression Mitochondrial inheritance

42. Pedigree manifesting maternal inheritance of LHON