Human Mitochondrial DNA

Features of Human Mitochondrial DNA

                           

·         Is circular, double-stranded, and composed of heavy (H) and light (L) chains or strands 

·         Contains 16,569 bp

·         Encodes 13 protein subunits of the respiratory chain (of a total of about 67

                Seven subunits of NADH dehydrogenase (complex I)

                Cytochrome b of complex III
                Three subunits of cytochrome oxidase (complex IV)
                Two subunits of ATP synthase

·         Encodes large (16S) and small (12S) mt ribosomal RNAs

·         Encodes 22 mt tRNA molecules

      Genetic code differs slightly from the standard code

                UGA (standard stop codon) is read as Trp
                AGA and AGG (standard codons for Arg) are read as stop codons

·         Contains very few untranslated sequences

·         High mutation rate (5 to 10 times that of nuclear DNA)

·         Comparisons of mtDNA sequences provide evidence about evolutionary origins of primates and other species

Mitochondrial DNA Inheritance

·         inheritance is only via the maternal line as the sperm contributes no cytoplasm to the zygote

·         all children of affected males will not inherit the diseases

·         all children of affected females will inherit it

·         generally encode rare neurological diseases

·         poor genotype:phenotype correlation - within a tissue or cell there can be different mitochondrial populations - this is known as heteroplasmy)

Histology

·         muscle biopsy classically shows 'red, ragged fibres' due to increased number of mitochondria

Mitochondrial DNA disorders :

·         Leber's hereditary optic neuropathy (LHON) - Bilateral subacute or acute painless optic atrophy

·         MELAS syndrome: mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes

·         MERRF syndrome: myoclonus epilepsy with ragged-red fibres in muscles, ataxia, 

·         Kearns-Sayre syndrome: onset in patients < 20 years old, external ophthalmoplegia, retinitis pigmentosa, heart block, ataxia

·         NARP, Leigh disease - neurogenic weakness, ataxia, retinitis pigmentosa

·         Pearson syndrome - pancreatic insufficiency, pancytopenia, lactic acidosis 

·         Chronic progressive external ophthalmoplegia - late-onset bilateral ptosis, ophthalmoplegia, proximal muscle weakness, exercise intolerance