Researchers Unravel Mystery of T-Box Genes' Role in Genetic Syndomes

Researchers Unravel Mystery of T-Box Genes' Role in Genetic Syndomes

Aug 10, 2003 6:00 PM

U OF U RESEARCHERS UNRAVEL MYSTERY OF T-BOX GENES' ROLE IN RARE GENETIC SYNDROMES ASSOCIATED WITH BIRTH DEFECTS

University of Utah geneticists, with the help of mutant zebrafish, have unraveled a conundrum associated with human syndromes that lead to limb and facial deformities, heart malfunctions, and other birth defects.

The syndromes are associated with defects in different members of a set of genes called T-box genes, which regulate development of organs or regions of the body. Since expression of T-box genes is found in many areas of the developing human body, researchers had been stumped by a fundamental question: Why were birth defects associated with these genes caused in only certain, limited regions?

The U researchers disabled T-box genes in zebrafish embryos and studied the most immediate changes that occur as a consequence of T-box gene malfunction--an experiment that can be performed far more readily in the fish embryo than in embryos that develop inside the mother, as mammals do. Their experiments revealed that individual T-box genes played different kinds of roles in different regions of the body. Further, the group uncovered one reason for the emergence of these multiple roles.

The researchers noted that several T-box genes are often expressed together in regions of the embryo and they appear to be used in overlapping domains so that a quilt-like pattern of the T-box genes is generated.

It is the combination of T-box genes used in a tissue that determined how it developed--when two or more T-box genes are used together, the genes alter each other's function, the U researchers showed. Thus, the specific job of each T-box gene depends on the partner T-box genes that are being used with it, and the key to the function of a T-box gene in the development of an organ is the earlier creation of the quilted pattern of multiple interacting T-box genes.

The study, published in the Aug. 5 issue of The Proceedings of the National Academy of Sciences, not only sheds light on some birth defects, but indicates that T-box genes can act together to generate a code that determines what steps in development should occur in a particular region of the body, according to David J. Grunwald, Ph.D., associate professor of human genetics at the U School of Medicine and Eccles Institute of Human Genetics.

"We tend to imagine that each gene has one principal function," said Grunwald, corresponding author of the study. "The T-box genes appear to change their jobs, depending on what other members they're partnering with. Therefore, to understand the clinical repercussions of a T-box gene defect, it is not enough to know only when and where the affected gene may be used. We will need to understand use of the gene in the context of its potential interacting T-box partners."

Grunwald notes that the central role of T-box genes in coordinating formation of portions of the body has only been recognized recently. There are approximately 20 such genes in backboned animals (vertebrates), and defects in five of these have already been linked to congenital syndromes in humans:

--Holt-Oram Syndrome - characterized by malformed bones in the thumbs and forearms, as well as heart abnormalities, including improper transmission of electrical impulses.

--Ulnar-Mammary Syndrome - associated with abnormal development of limbs, milk glands, and genitals.

--DiGeorge Syndrome - accompanied by heart, facial, thyroid, and other defects.

-- Isolated ACTH deficiency (IAD) - a defect in pituitary gland function.

--X-linked cleft palate with ankyloglossia - a defect in formation of the palate and tongue.

A complex challenge to a growing embryo is how to coordinate the origin of body elements, such as finger digits or heart chambers, with their correct placement. Grunwald hypothesizes that the quilt-like pattern of use of the T-box genes and the fact that combinations of them create new regulatory functions reflect a central role of the T-box genes: to subdivide developing organs or regions of the embryo into smaller tissue regions each of which will develop with specialized form and function.

Over the past 25 years, only HOX genes were known to function in this manner. But now the Utah researcher suspects: "We should come to anticipate that other families of regulatory genes may also form interacting networks that have a primary function in coordinating regionalization and cell differentiation. Moreover, from an evolutionary point of view, small changes in the generation of the quilt pattern of T-box genes might have large effects on animal form."

Along with Grunwald, authors of the study include Lisa M. Goering, Kazuyuki Hoshijima, Barbara Hug, and Brent Bisgrove of the U School of Medicine Department of Human Genetics, and Andreas Kispert of the Max-Planck Institute for Developmental Biology, Freiburg, Germany.

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