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)