Cutting-Edge Research Uses New Technologies to Unravel Diseases

YCCI has developed a highly effective partnership with the W.M. Keck Foundation Biotechnology Resource Laboratory to provide genomics and proteomics expertise and equipment that is helping investigators solve puzzles that have vast implications for treating a variety of diseases.

Led by Murat Gunel, the Nixdorff-German Professor of Neurosurgery, Genetics and Neurobiology, a team of researchers has discovered that the mutations in a single gene critical to the development of the cerebral cortex can cause a number of brain deformities that were previously thought to be unrelated. Reporting online August 22 in the journal Nature, researchers used whole exome sequencing, a technology pioneered at Yale that enables the rapid sequencing of all the protein coding gens in the human genome, to identify mutations in the gene that encodes WCR62, a protein critical for brain development. The team initially studied two cousins from Turkey who were born with extremely underdeveloped cerebral cortices and other deformities that were believed to be separate disorders. Using instruments funded by Yale’s Clinical and Translational Science Award (CTSA), they discovered mutations in both copies of the gene that encodes WDR62. They later identified six additional families with the same mutations.

“Because patients with mutations in this gene were only a fraction of the total cohort, this gene would have been very difficult to map and identify using traditional approaches,” said Richard Lifton, Sterling Professor and Chair of Genetics at Yale, whose lab developed the exome sequencing and analysis methods used for the study. Such approaches may help to unravel the genetics of other developmental brain disorders such as autism and mental retardation.

Another study utilized CTSA-funded instrumentation to map and identify disease-causing mutations in the rare skin disease ichthyosis with confetti. The study found that the spots of normal skin that appear in patients with the disease are caused by the recombination of chromosomes during cell division. The exchange between chromosomes results in cells with either two mutant copies or no mutant copies of the gene encoding the protein keratin 10, which accounts for the sporadic appearance of normal skin. Published in the August 26 issue of Science Express, the study describes how in all affected patients the normal tail end of the keratin 10 protein is replaced by a protein sequence that causes it to end up in the wrong part of the cell. Keith Choate, assistant professor of dermatology and first author of the paper and Lifton, senior author of the paper, believe this contributes to both the severity of the disease and the appearance of the clones of normal skin. They hope the discovery will lead to a way of mimicking this process to develop treatments for other genetic diseases.

In another study published in the August 7, 2009 issue of Cell, Lifton and Jesse Rinehart, associate research scientist in genetics, led a team that discovered how a protein within most cell membranes maintains normal cell size, a breakthrough that has implications for a variety of diseases, including sickle cell anemia. Researchers used innovative quantitative proteomics technologies to identify phosphorylation sites that switch potassium chloride co-transporter proteins on or off in response to environmental changes, thereby causing water movement in or out of the cell and modulating cell volume. The study utilized a triple quadrupole mass spectrometer and UPLC system in Keck Lab that was purchased through funding provided by the CTSA award. In 2009, Yale opened a new Center for Genome Analysis on its west campus that is closely linked to the Keck Lab.