Wmed/Genetic Foundations/Multifactorial Inheritance: Environmental Factors

Mitochondrial genome
The mitochondial genome contains mtDNA and has 37 genes spanning 16.5kbp
 * Contains 37 genes, all essential
 * 13 involved in oxphos
 * 22 tRNA <--reduced redunancy
 * 2 rRNA <--reduced amount of tRNA isoacceptors necessary
 * Prone to somatic mutations that are not passed to future generations

Mitochondrial inheritance patterns
Conditions affect males and females, but always maternally inherited
 * Mitochondrial genetic bottleneck
 * definition

Replicative segregation

 * Mitotic/meiotic chromosomal segregation is not tightly controlled
 * Multiple copies of mtDNA replicate and randomly sort
 * Random distribution among daughter cells

Homo/heteroplasmy

 * Homo: daughter cell mitochondria population is uniform
 * Hetero: mixture of mutated and nonmutated mitochondria

Mitochondrial diseases
Predictably so, most mitochondrial diseases involve oxphos inhibition
 * Cancer
 * limited evidence for an association
 * Mutations may increase ROS that mitochondria are not prepared to fix (somatic mutations)
 * Cyclic vomiting syndrome
 * Recurrent nausea, vomiting, lethargy
 * ANS but unknown mechanism
 * Cytochrome C oxidase (complex IV) deficiency
 * Mutations in MT-CO1,2,3 affect skeletal muscles, heart, brain, liver
 * Kearns-Sayre syndrome
 * Single, large (somatic) deletion of mtDNA
 * Most commonly 4,997bps (12 genes, oxphos, energy drops)
 * Affects eyes: ophthalmoplegia (muscle weakness) and retinopathy
 * Leber hereditary optic neuropathy
 * Missense mutations in MT-ND1,4,4L,6, coded for complex I
 * Leigh syndrome
 * Mutation in MT-ATP6, coded for complex V and tRNA
 * Progressive brain disorder: developmental delay, muscle weakness, movement problems, breathing difficulties
 * Often autosomal recessive inheritance, 20% mitochondial
 * Maternally inherited diabetes and deafness
 * Mutation in MT-TL1, TK, TE
 * Hearing loss (especially high tones), slow protein production, inability to trigger insulin release
 * Mitochondrial complex III
 * Mutation in MT-CYB (encodes cytochrome b)
 * Weakness, affects liver, kidney, heart, brain
 * MELAS
 * Mutation in MT-ND1, ND5, TH, TL1, TV
 * Missense in MT-TL1 causes 80% of cases
 * encephalomyopathy, lactic acidosis, stroke-like episodes
 * Myoclonic epilepsy w/ ragged red fibers
 * Mutation in MT-TK, TL1, TH, TS1
 * MT-TK missense mutation causes 80% of cases
 * myoclonus (twitches), myopathy, spasticity
 * NARP
 * Mutation in MT-ATP6 (ATP synthase subunit)
 * Neuropathy, ataxia, retinitis pigmentosa
 * Nonsyndromic deafness
 * Mutations in MT-RNR1, TS1
 * MT-RNR1 encodes 12s rRNA and mutations make it similar to that of bacteria (aminoglycosides target it)
 * Pearson Marrow-pancreas syndrome
 * De novo deletion of mtDNA (similar to and may often become Kearns-Sayre)
 * Affects blood cells and pancreatic development
 * Generally not inherited (somatic mutations during embryonic development)
 * Progressive external ophthalmoplegia
 * mtDNA deletion/mutation
 * Ptosis (eyelids dropping)