In 1963, physician Angelo M. DiGeorge discovered a set of birth defects that often affects the heart and is behind a host of other problems. These can include mild learning disabilities, severe retardation, and facial abnormalities such as down-slanting eyes, a bulbous nose, and cleft palate. Clinicians estimate that DiGeorge’s syndrome affects 1 in 4,000 newborns and is the second most common cause of congenital heart defects.
Now, researchers report that defects in either of two specific genes may be behind the syndrome. In an article in the March 1 Nature and two in the March Nature Genetics, three research teams working with mice describe disabling either of two genes, Tbx1 and Crkol, to reproduce many of the syndrome’s effects.
Although researchers had pegged the syndrome’s genetic basis to deletions in various sections of human chromosome 22 in 1978, the specific genes responsible have been elusive.
“It’s an exciting business. There have been some 20 or more genes that have been [suspects], and none of them panned out,” says DiGeorge at Temple University Children’s Medical Center in Philadelphia.
“[Scientists] had basically hit a wall in traditional mapping,” says Seigo Izumo, a cardiovascular researcher at Beth Israel Deaconess Medical Center in Boston. Instead of searching for individual genes in people, the authors of all three papers modified mice so the animals would have defective copies of either Tbx1 or Crkol.
In one of the Nature Genetics studies, Loydie A. Jerome and Virginia E. Papaioannou of Harvard Medical School found that embryonic mice without Tbx1 have malformations of the aortic arches, which become the major arteries leaving the heart.
In the report appearing in the March 1 Nature, a group led by Elizabeth A. Lindsay at the Baylor College of Medicine in Houston found similar effects in their own version of mice without Tbx1.
Both groups found that Tbx1 must be disabled on both copies of the chromosomes that bear it to produce the heart defect. In people, however, it takes only one faulty chromosome to produce DiGeorge’s, the researchers say.
The human version of Tbx1, specified as TBX1, has always been considered a good candidate for the main cause of the syndrome, says Marcia L. Budarf, leader of the lab at the University of Pennsylvania School of Medicine that first described the gene in humans. “It’s clear that TBX1 is important to this syndrome, but it might not be the whole story in humans,” she says. Budarf has studied over 100 DiGeorge’s patients who don’t have TBX1 deletions.
Akira Imamoto of the University of Chicago and his colleagues focused on Crkol–the mouse equivalent of the human gene CRKL, which is sometimes absent from patients with DiGeorge’s syndrome. The embryos that were missing the gene had heart defects and facial abnormalities like those of patients with the syndrome, they report in Nature Genetics.
The effects of the syndrome and their severity vary even between people with identical deletions of chromosome sections. In many cases, the syndrome is so mild that it goes unrecognized. “We have adults who never knew they had it until they had an affected child,” says Donna McDonald-McGinn a genetic counselor at the University of Pennsylvania Children’s Hospital.
Finding the genes responsible could lead to genetic tests for the syndrome and help refine understanding of embryonic development, says Izumo.