Having found the MAK mutation in one patient, UI researchers led by Edwin Stone, M.D., Ph.D., a Howard Hughes Medical Institute investigator and director of the UI Institute for Vision Research, screened the DNA of 1,798 patients with RP and identified 20 additional individuals with the same MAK mutation. This result suggests that the new MAK mutation accounts for about 1.2 percent of RP cases in the general population. Interestingly, all 21 of the RP patients with the MAK mutation were of Jewish descent, suggesting that the mutation may be a significant cause of RP in this population.
Work in the lab of Robert Mullins, Ph.D., UI associate professor of ophthalmology and visual sciences, showed that MAK protein was produced in the cells most affected by RP. These findings prompted Tucker and colleagues to make iPSCs from the original patient.
"Induced pluripotent stem cells allow us to generate affected tissue from patients with genetic disorders and analyze how specific genetic mutations cause disease," Tucker said. "It's particularly powerful when we are looking at inaccessible tissues such as the retina and brain which are not usually biopsied in living individuals."
Although the MAK gene was previously thought to have 13 protein-coding segments known as exons, when the UI team cloned and sequenced the MAK gene, they discovered a new version of the gene found only in the retina, which has an extra protein-coding exon.
The team also found that the MAK mutation, which involves an insertion of a large piece of DNA into the MAK gene, disrupts the gene in such a way that retinal cells lose the ability to make the longer version of MAK protein.
"What we found was a new retina-specific exon; no other tissue that we tested had this version of the protein-coding transcript" Tucker said. "This is important because the gene mutation identified prevents the production of the retina-specific MAK protein.
|Contact: Jennifer Brown|
University of Iowa Health Care