Researchers find cause of common genetic disorder

Researchers from the University, Columbia University and Baylor University have separately identified genetic abnormalities in mice that are responsible for the multiple malformations associated with a human disorder called DiGeorge syndrome, which is the second most common genetic cause of heart defects.

A team led by Akira Imamoto, Assistant Professor in the Ben May Institute for Cancer Research and the Center for Molecular Oncology, found that mice lacking a functional version of a gene known as CRKL have multiple defects of the heart, thymus and facial structures. These defects closely resemble DiGeorge syndrome.

The research teams from the other institutions focused on a different gene, called TBX1, which regulates other genes that control the development of the blood vessels closest to the heart.

Both genes are found in a small region of the mouse chromosome 16, which is similar to the human chromosome 22.

Patients with DiGeorge syndrome often have a small piece missing from chromosome 22. Researchers have long searched for the 30 or so genes that are lost when a portion of that chromosome is missing. These studies appear to pinpoint which of those genes are the key players in the development of this disease.

“Our finding, especially in combination with these other studies, suggests that several independent genes contribute to the complex developmental defects seen in DiGeorge syndrome,” said Imamoto. “These mice should provide an extremely valuable model for studying the mechanisms that underlie these congenital defects.”

DiGeorge syndrome affects one in every 4,000 live births. It causes several symptoms, ranging from structural defects of the heart and its vessels, to abnormalities of the thymus and parathyroid glands, to facial irregularities, such as cleft palate.

Both genes appear to help regulate the normal development of structures in the upper chest and the neck. During gestation, a population of cells from an embryonic structure known as the neural crest migrates into the region above the heart and contributes to the growth of blood vessels, the thymus, the parathyroid gland and other structures. TBX1 appears to control the expression of other genes that influence this process. CRKL may act later in the developmental process, regulating how these cells signal and connect with each other.

Deborah Guris and Judith Fantes of Chicago and David Tara and Brian Drucker of Oregon Health Sciences University also contributed to the CRKL paper, which was published in the March issue of Nature Genetics.