WIKIMEDIA, CHRISTOPH BOCKA rare neurological disorder is caused by a single mutation in the CLP1 gene, according to two papers published this week (April 24) in Cell. One team, led by James Lupski at the Baylor College of Medicine in Houston, Texas, studied the disorder in children as well as in a mouse model. The other team, co-led by Murat Gunel of Yale University, Frank Bass of the Academic Medical Center in Amsterdam, the Netherlands, and Joseph Gleeson of the University of California, San Diego (UCSD), focused on tracing the genetic defect to its origins.
Babies with this disorder are born with small, deformed brains, are likely to have siezures, never learn to talk, and have progressive muscle weakness. The Baylor team used exome sequencing to identify a single mutation in the CLP1 gene that affected five families in Turkey. Study coauthor Josef Penninger of the Austrian Academy of Sciences in Vienna demonstrated that, in mice, the gene affected the survival of critical brain stem cells.
“We had patients with an interesting phenotype (symptoms) and a novel gene but no evidence from the lab that these mutations are disease-causing. They had a model organism, a mouse, but they didn't have evidence that it affected people. It was a perfect storm,” study coauthor, geneticist Wojciech Wiszniewski of Baylor, told Reuters.
The other team performed exome sequencing on 2,000 samples from families affected by the disorder, also finding it was caused by a mutation in CLP1. The researchers traced the defect back 16 generations to four independent mutations that occurred about 400 years ago, at the height of the Ottoman Empire. “What we found particularly striking, when considering the two studies together, is that this is not a condition that we would have been able to separate from other similar disorders based purely on patient symptoms or clinical features,” UCSD’s Gleeson said in a statement.