On Campus

25-Year Dwarfism Study Ends with Gene, Cause Identified

By Cecelia Fielding

A BYU professor’s 25-year search for the cause of a lethal form of dwarfism in mice–and potentially in humans–has resulted in both the isolation of the affected gene and the identification of the “missing ingredient” causing the mutation.

Zoology professor Robert E. Seegmiller has been working with a strain of mice carrying chondrodysplasia, or cho, a minor but always fatal type of dwarfism. When the dwarfism appears in the offspring, the mutant mice exhibit such characteristics as cleft palate, tracheal and lower jaw abnormalities, short legs, and severe respiratory defects. Because of the lack of adequate bone formation, particularly in the rib cage, the animals die at birth of respiratory complications.

“In normal development, cartilage cells line up in columns, leading to the formation of regular bone tissue,” Seegmiller explains. “In the mutant mice, however, the cartilage cells are highly disorganized and the bones develop poorly.”

A gene-mapping study carried out in collaboration with Cory Teuscher, a BYU associate professor of microbiology, identified mouse chromosome 3 as the likely cause of the cho mutation. Further analysis by Harvard Medical School scientists headed by Bjorn Olsen revealed that chromosome 3 was also the location of the gene for type XI collagen, a minor component of normal cartilage tissue. Detailed genetic studies then showed that the type XI collagen gene was defective, resulting in the absence of the collagen in the mutant mice.

While type XI collagen is a minor component, Seegmiller hypothesizes that it combines with type II collagen, a major cartilage collagen, to allow for the normal development of the cartilage. “The absence of type XI collagen allows the type II collagen fibril to expand unchecked,” he says. This expansion means the fibrils grow excessively thick and in an unorganized manner, causing bones to develop shorter and thicker than usual.

“This means we have now identified a minor collagen that plays a major role in the normal development of the skeleton,” he explains. Before this discovery, researchers were unsure of the function of type XI collagen. “One of the most interesting things about examining genetic defects is that they help us better define what is normal, particularly on a molecular level.”

The results could also pay dividends in human genetic research. “There is a human genetic defect, called Stickler syndrome, in a Dutch family line that involves type XI collagen,” he says. “Our cho research could help explain and diagnose it as well as other minor forms of dwarfism.

It could be useful to human carriers of such defective genes in helping identify that gene in them and their offspring, now that we know what we’re looking for.”

Seegmiller first encountered the mutant mice as a graduate student at McGill University in Montreal, Canada. He did his doctoral dissertation on the physical characteristics of the cho mice, and when he joined the BYU Zoology Department in 1972, the strain of mice came with him. Since then he has coauthored more than one dozen publications dealing with the effects and mechanisms of the skeletal defect.

“My question for the past 25 years has been: What is the missing ingredient, the defective component in the cartilage?” he says. To answer the question, Seegmiller and a series of graduate students over the years have been painstakingly analyzing the dozens of components of the mouse cartilage.

“We noticed early on that, in the mutant mice, the collagen fibril was much thicker than normal throughout the animal’s cartilage, making it a good candidate for the cause of the mutation,” he says.

His search was aided by some exciting new developments in science. “When the technology became available, we stopped looking at the macromolecular level and decided to map the gene in hopes of finding a candidate that would be associated with the mutation,” he says.

Jackson Laboratories in Bar Harbor, Maine, provided a strain of mice that had retrovirus markers placed on 13 of their 21 chromosomes.

“By crossing their strain of marked mice with our mice carrying the cho gene, we were able to make a two-generational cross. Now, whenever the affected mutant mice appear, the possibility exists to identify the chromosome carrying the defective gene.”

Seegmiller benefitted not only from good science, but from a little luck as well. “We only had markers on just over half the chromosomes, which meant the gene-mapping experiment could have easily failed,” he admits.

But, fortunately, after six months of cross breeding and analyzing more than 100 mutant fetuses, Seegmiller and his team were able to map the gene. “The experiment showed a close relationship between the cho mutation and what was called the EMV27 retrovirus marker on the third chromosome,” he says.

“The pieces of the puzzle were rapidly fitting into place as we realized that the marked region on mouse chromosome 3 corresponded to a specific region on human chromosome 1 that encoded a gene for type XI collagen, thus pointing to type XI collagen as the potential cause of the mouse mutation.”

One of his doctoral students, Yefu Li, who is now working in the laboratory of Bjorn Olsen at Harvard, was able to sequence the gene, or analyze the genetic code that gives instructions for producing type XI collagen.

“Li found that cytosine, one of the elements of the genetic code, is missing in the formula, altering and ultimately stopping the formation of type XI collagen and causing the defects associated with this mutation.”

As a teratologist, or a researcher of birth defects, Seegmiller has continued his studies, looking at a similar type of mouse dwarfism called Disproportionate micromelia, or Dmm, and the research with this
strain has recently produced another find.

“With the same group of scientists, this time including graduate student James Pace, we were fortunate to discover in the Dmm mice a mutation involving a deletion in the genetic code for type II collagen, the major cartilage collagen. This underscores the importance of the type II–
type XI interaction in skeletal development. And this has all types of ramifications in the understanding of normal skeletal development as well as abnormal development.”

The Dmm discovery will be featured later this year in the science journal Developmental Dynamics. Last year, the national science journal Cell covered the cho find.

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