Mitochondrial DNA (mt
DNA) supplies extranuclear (cytoplasmic) genes which program the manufacture of 13 of the 67
peptides of the mitochondrial respiratory
enzymes. The remaining 54 are coded by nuclear
DNA. All human children and adults, male and female, are entirely dependent on the cytoplasm of the ovum for their
complement of mt
DNA; the sperm contributes none. Accordingly, mutations in the mt
DNA in a mother's ova will be passed on to all her children, although not all are clinically affected.
Leber's hereditary optic neuropathy is in most cases due to a mutation that leads to the replacement of
guanine by
adenine at position 11778 in mt
DNA. This causes
histidine to be inserted instead of the normal
arginine at the site of the 340th
amino acid in the respiratory
enzyme NADH subunit 4, hence its defective function. Other point mutations in the mt
DNA coding for
polypeptides of the respiratory chain complex or controlling sequences coded by mt
DNA have been found in other families with
Leber's hereditary optic neuropathy.
Mitochondrial DNA is the site of other mutations as well. For ophthalmologists, the most important of these is the rare
Kearns-Sayre syndrome (
pigmentary retinopathy plus
muscular dystrophies, especially of the extraocular muscles).
Kearns-Sayre syndrome is due to deletions in the mt
DNA, which vary in size and so affect a number of different respiratory
enzymes, hence the variable manifestations. Cases are usually sporadic because the disease is often so severe that affected individuals do not reproduce if they survive, but in some cases inheritance from the mother has been reported.