Genetic aberration helps explain variation in cystic fibrosis

At the annual meeting of the Americal Society for Human Genetics in Los Angeles, Hopkins researchers will reveal the existence of specific short repeats of particular genetic building blocks in the gene at the root of cystic fibrosis, an inherited and often fatal lung disease. The researchers will also show how the repetitious pattern may help predict the disease’s severity.

Cystic fibrosis, or CF, stems from mutations in a gene called CFTR, short for cystic fibrosis transmembrane conductance regulator. When specific mutations appear in both copies of the gene, a sticky mucus builds up in the lungs, making breathing difficult and trapping bacteria that can cause serious and deadly infections.

One CFTR mutation, known as 5T, doesn’t always cause CF even when 5T and one of the traditional CF-causing mutations are present, a person can be disease-free. However, there’s no good way to predict whether the 5T combo will lead to disease or whether the person will be perfectly healthy.

In a presentation Thursday, Nov. 6, at 2 p.m., graduate student Tim Hefferon is scheduled to report that repeats of two sets of genetic building blocks thymine (T) by itself or a thymine-guanine (TG) combination appear in the CFTR gene in certain combinations that affect disease status. The TG repeat is typically 9 to 13 sets long, followed by a set of 5, 7 or 9 Ts, but some combinations are more likely than others. In particular, scientists have only observed combinations of T and TG repeats that add up to 27 to 31 building blocks. In theory, combinations could be as short as 23 and as long as 35 building blocks.

In an 8 a.m. presentation on Saturday, Nov. 8, graduate student Josh Groman is scheduled to report that the presence of a TG repeat in CFTR that is 12 or 13 sets long is much more common in people who have 5T and a CF-causing mutation and lung disease than those who have the mutations but are healthy. The researchers conclude that establishing the length of this TG repeat may help predict disease severity in people with 5T and another CFTR mutation. Roughly 10 percent of the general population has the 5T mutation, but the vast majority of those do not also have a traditional CF-causing mutation.

The principal investigator of these studies, Garry Cutting, Ph.D., professor of pediatrics and medicine at Johns Hopkins, directs Hopkins’ DNA Diagnostic Laboratory as well as the Cystic Fibrosis Foundation Genotyping Center at Johns Hopkins.