Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) s
ID: 175040 • Letter: M
Question
Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome iscaused by an A G transversion at position 3243 in the human mitochondrial genome. Nearlyall individuals who have MELAS syndrome are heteroplasmic for the mutation. Also, there issubstantial variation for clinical manifestations of the syndrome among people who inherit themutation. In 1994 Matthews et al. traced the mutation through four generations in a family.They found that the amount of mutant mitochondrial DNA in tissues varied within an individualand that the proportion of mutant mitochondrial DNA in a tissue was correlated with clinicalmanifestations of symptoms in that tissue. For example, a woman who died of cardiomyopathy(disease of the heart muscle) had a higher proportion of mutant mitochondrial DNA in her heartthan in most other organs. Explain why the proportion of mutant DNA may be greater in oneorgan than another in the same individual. Also explain why heteroplasmy may cause partial
penetrance and variable expressivity for mitochondrial genetic disorders.
Explanation / Answer
The proportion of mutant DNA may be greater in one organ than another in the same individual due to differential expression of the gene in the different organs.
A cell can have some mitochondria that have a mutation in the mtDNA and some that do not. This is termed heteroplasmy. Since, heteroplasmy is the presence of more than one type of organellar genome (mitochondrial DNA or plastid DNA) within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Penetrance is described as either “complete” or “incomplete.” For example, individuals who carry the gene for tuberous sclerosis have an 80% chance of expressing the disorder. Penetrance may also be dependent on a susceptible individual’s current age. For example, 20% of all gene carriers for myotonic dystrophy express the gene to some degree by age 15, while 80% of all gene carriers express it by age 60. The penetrance varies as the expression of the gene may vary due to various factors like: inhibition of gene expression (Wallaced, 2013). Since penetrance depends on the degree of expression and the degree of gene expression can be down regulated by gene silencing mechanisms include a variety of transcriptional and posttranscriptional like, siRNA, shRNA, etc.