A Brigham Young University 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.

Robert E. Seegmiller's work with a strain of mice affected with chondrodysplasia or cho, a minor but always fatal type of dwarfism, is featured in the Feb. 10 issue of the national science journal Cell.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.

Seegmiller's research with the cho mice determined that an absence of type 11 collagen, one of the minor building blocks for normal cartilage tissue, results in excessive growth of the major cartilage collagen known as type 2 collagen.

A gene-mapping study carried out in collaboration with Cory Teuscher of the BYU microbiology department and graduate student Bryan Wardell identified mouse chromosome 3 as the site of the cho mutation. Detailed molecular genetic linkage analysis demonstrated that the cho mutation was in fact tightly linked to the type 11 collagen gene on chromosome 3.

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

While type 11 collagen is a minor building block, Seegmiller hypothesizes that it combines with the more prevalent type 2 collagen to allow for the normal development of the cartilage. The absence of type 11 collagen allows the type 2 collagen fibril to expand unchecked, he said.

This means they have identified a minor collagen that plays a major role in the normal development of the skeleton, he said.

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 11 collagen, he said. Their research could help explain and diagnose it as well as other minor forms of dwarfism.