The Organism as a system

Transcription

1 The Organism as a system PATIENT 1: Seven-year old female with a history of normal development until age two. At this point she developed episodic vomiting, acidosis, epilepsy, general weakness, ataxia (stiff, unsteady gait), and dystonia (movement disorder characterized by involuntary muscle contractions). PATIENT 2: Fifty-year old male with sudden onset headaches and seizures. Patient has a history of diabetes and deafness. Magnetic resonance imaging (MRI) detected bitemporal lesions.

2 A little more detail

3 What do these affected organ systems have in common? Both patients show symptoms of MELAS, a classic mitochondrial disorder, which is associated with an A>G point mutation at locus 3243 (L1 gene).

4 Organizing our thinking around the problem

5 What is the relationship between mitochondria and this disease phenotype? 16,569 bp 37 genes 24 needed for mt DNA translation 2 rrnas 22 trnas 13 subunits of ETC

6 Amplifying DNA using PCR: Polymerase

7 What is the relationship between mitochondria and this disease phenotype? 16,569 bp 37 genes 24 needed for mt DNA translation 2 rrnas 22 trnas 13 subunits of ETC

8 What is the rela+onship between mitochondria and this disease phenotype?

9 How can something so small be such a big deal? -- Dan Sharer The flow of genetic information: a b a a DNA mrna PROTEIN b trna rrna a b c d e f g h i What types of proteins are coded for by mitochondrial DNA?

10 What is the rela+onship between mitochondria and this disease phenotype?

11 Explaining the rela+onship between mitochondria and this disease phenotype? Organism headaches and seizures, diabetes and deafness Tissue Cell episodic vomi+ng, acidosis, epilepsy, general weakness, ataxia Organelle Molecule How can something so small Be such a big deal? -- Dan Sharer

12 mt DNA Gel Analysis MWM wt cntrl mut patient patient 2 cntrl 1

13 Organizing our thinking around the problem

14 One more level of complexity: nuances of mitochondrial genetics Mitochondrial DNA is maternally inherited. Multiple tissues can show symptoms of mitochondrial disorders because of random distribution of mitochondria during cell division During development and during growth and repair of tissues. There are 1000s of mtdna molecules in each cell, and in general, pathogenic mutations of mtdna are present in some but not all of these genomes. As a result cells harbor both normal (wild-type) and mutant mtdna, a situation known as heteroplasmy. (0.42% - 78%) In humans, there is variable sensitivity of different tissues to decreased ETC output. This is known as threshold affect. Essentially, some tissues are more sensitive to mitochondrial disorders than others.

15 Organizing our thinking around the problem

16 Another line of evidence to ponder while the gel runs Patient 1 (girl): A family history has been taken going back to the patient s grandparents on her mothers side. No similar symptoms have occurred in the patient s siblings (patient has twin older brothers), patient s parents, or patient s mother s parents. Patient 2 (male): A family history has been taken going back to the patient s grandparents on his mother s side. Patient s brother was found to have asymptomatic mild lactic acidosis. Patient s mother had diabetes, exercise intolerance, and ptosis (drooping eyelids). Patient s maternal uncle died of a stroke at age 37, and had multiple health issues (poorly defined). Patient s maternal grandmother had diabetes and possibly other symptoms. The patient s father has rheumatoid arthritis, but no history of diabetes or neurological problems.

17 Pedigrees Patient 1 (7 year old girl) Patient 2 (50 year old man)