Scanning the human genome for a single disease-causing mutation is like taking a copy of War and Peace in a foreign language and searching for one misspelled word—a daunting and time-consuming task. But by narrowing the search in the right way, says one HHMI scientist, finding a mutation for even the rarest of diseases doesn’t have to be difficult.
HHMI investigator Friedhelm Hildebrandt, of the University of Michigan, used an innovative combination of genetic techniques to find a mutation that causes kidney failure and blindness in affected children. The mutation is known to exist in only 10 families worldwide.
For years Hildebrandt’s team has been collecting genetic samples from families with Senior-Loken syndrome, for which no treatment is available. They have more than 600 families in their database and have linked nine different genes to the disease. But there were still unexplained cases.
Rather than scrutinizing the entire genomes of affected individuals for mutations, the researchers narrowed their search. First, they sequenced only exons—stretches of DNA that code for proteins—which make up only 1 percent of the genome. Then, the team focused on 828 genes known to contribute to the function of cilia, cellular structures affected by the nine previously identified genes. Finally, they searched their database for matching DNA regions in two siblings affected by Senior-Loken syndrome.
The techniques made the search much more efficient than traditional methods, and it paid off: the team found mutations in a gene called SDCCAG8 in 10 families affected by the syndrome. The group had been unable to find this gene despite a 6-year search, because of the syndrome’s rarity. So-called “exon capture” allowed its identification in a single family within 6 months.
The exact role of the SDCCAG8 protein in the syndrome isn’t known, but it is involved in the function of cilia—sensory extensions of a cell—in the kidneys and eyes, the scientists reported online September 12, 2010, in Nature Genetics. Furthermore, normal kidney cells form hollow, symmetrical spheroid structures when grown in a gel, but cells lacking SDCCAG8 form irregularly shaped spheres. Hildebrandt hopes they can use this trait to test compounds that might restore SDCCAG8’s function.