The woman told researchers that a number of her female relatives had the same problem. Further study of the family revealed a high frequency of high blood pressure and cholesterol.
"That's when the real saga began," said Lifton. "The family was extraordinarily cooperative, and we eventually studied 142 relatives. When we looked at the pattern of these pathologies, we found there was a whopping excess of affected individuals on the maternal lineage."
Such a pattern immediately suggested a defect in the mitochondrial genome, because those genes are uniquely passed from mother to offspring, unlike the rest of the cell's genome, which is contained in the nucleus.
Detailed sequencing of the mitochondrial genomes of family members revealed a specific mutation in all affected people. That defect was the substitution of a single DNA unit, or base, in the gene that coded for a specific transfer RNA (tRNA) in the mitochondria.
Transfer RNAs are critical carrier molecules that ferry amino acids during the constructions of proteins in the cell. During the translation of genetic material to a protein, a tRNA latches onto a specific amino acid that it was designed to carry and transports it to the site of protein synthesis. There, it docks precisely with the messenger RNA that is the protein's blueprint and unloads its amino-acid cargo, which can then be incorporated into the elongating protein chain.
The defective base the researchers pinpointed was in the gene for the tRNA that transports the amino acid isoleucine. That defect distorted the docking region of the tRNA, preventing it from recognizing and attaching to the messenger RNA to deposit its isoleucine cargo. Thus, the faulty tRNA could lead to defects in a vast array of proteins that normally contain isoleucine, thereby contribu
Contact: Jennifer Michalowski
Howard Hughes Medical Institute