Compiled from lecture notes, this is a condense but detailed summary of the mitochondrial diseases covered in BHCS3009 module. All the information (and more) is available in one place in a logical order, easy to search and use for revision.
Non-traditional inheritance
• A number of familial diseases which do not conform to patterns expected of Mendelian inheritance
• Do not fit multifactorial inheritance
• 2 main explanations
o Genomic imprinting
o Mitochondrial inheritance
Mitochondria
• Principle sites of ATP production by processes of oxidative phosphorylation
• Most human cells contain several hundred mitochondria
• Mitochondrial DNA (mtDNA) consists of 16,569bp encoding 13 polypeptides, 22 tRNAs and 2
rRNAs
• 2-10 copies of mtDNA in each mitochondrion
• Most of the several hundred polypeptides in mitochondria encoded by nuclear genome
Mitochondrial DNA
• Replication and transcription controlled by
displacement loop – d-loop
Nuclear vs mitochondrial genome
Nuclear genome Mitochondrialgenome
Size (base pairs) 3200 Mb (3.2 x 109 ) 16.6 kb
No. molecules per cell 46 (23/24 different in F/M) thousandscopies of one molecule
Associated protein histones & non-histones largely free of protein
Number of genes ~21,000 protein-coding 37 (13 protein-codingplus 22 tRNAand
22,000+RNA genes ? 2 rRNAgenes)
Gene density 1 gene / 70-140 kb 1 gene / 0.45 kb
Repetitive DNA ~50% very little
Transcription geneby gene continuous
Introns in most genes none
% coding DNA ~2% ~93%
Codon usage different
Recombination at least once per pair of homologues not seen
per meiosis
Inheritance Mendelian (Y paternal) maternal
Mitochondrial function
• Mitochondrial respiratory chain complexes and the oxidative phosphorylation system (OXPHOS)
• Electron/proton pathways along these complexes
• 5 intramitochondrial enzyme complexes
• Complex 1 has 45 subunits, 38 nuclear encoded, 7 mitochondrial encoded
• Variants in any complex can affect function
Mitochondrial disease
• First identified in 1962
• Patient with structurally abnormal mitochondria and a loss of coupling between oxidation and
phosphorylation
• Mutations in genes that regulate mitochondrial functional, both in nuclear DNA and mtDNA
, • 1980s – relevance of mutated mtDNA to human disease
• Matrilinear inheritance applies to those disorders due to variants in mtDNA
• Pedigree of mitochondrial diseases
o Affected males cannot pass disease to his offspring
o Transmission of disease is only through female
o All her offspring, male and female, are affected
o Incomplete penetrance – skips generation where phenotype does not manifest but still
possess variant as next generation shows disease (carriers); affects pedigree analysis
• Largest class of inborn errors of metabolism with collective incidence of 3 in 10,000
• Progressive, debilitating diseases
• May manifest in utero, at birth, childhood or delayed adult onset
• Multisystem disease with very variable clinical progression – any unexplained, progressive,
multisystem illness should be evaluated for mitochondrial disease
• Care includes energy management, physical therapy, nutritional and emotional support
Mitochondrial disease genes
• Subsets of mitochondrial disease genes (338) according to functional roles
• Roles include
o mtDNA maintenance
o expression, translation
o mitochondrial dynamics
o substrate metabolism
o cofactor metabolism
• Modes of inheritance
o Autosomal dominance (AD)
o Autosomal recessive (AR)
o X-linked dominant (XD)
o X-linked recessive (XR)
Nuclear DNA and mitochondrial disease
• Mitochondrial proteins mainly encoded by nuclear genes
• Mutations here can have serious effects on respiratory chain function within mitochondria
• E.g., AR variants in genes encoding proteins in CytC system – SURF1
• E.g., G4.5 (TAZ) is XR – in males, results in Barth syndrome
• E.g., mitochondria myopathy, AD, caused by variants in POLG genes
• Heterogeneity must be present (not all mitochondria affected) else person will die (not viable for
life)
Leigh syndrome
• Clinical diagnosis based mainly on brain imaging, but considerable genetic heterogeneity
• Mutations in nuclear and mtDNA
o Genes in complexes I, II, III, IV or V deficiency
o Genes encoding mt tRNA proteins
o Components of pyruvate dehydrogenase complex
o Some forms of combined OXPHOS deficiency
• More than 90 genes implicated in disorder
Phenotypic heterogeneity
• Wide phenotypic spectrum within and between mt diseases
• Phenotypic variation determined by proportion of mitochondria containing mutation/variant
(depends on level of genetic heterogeneity)
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