Michael Naski has helped to identify a genetic mutation that can cause bones to stop growing, leading to a form of dwarfism.

Scientists often say success is part sweat, part serendipity. Physician Michael Naski agrees. In 1994, Naski won an HHMI fellowship to study a family of protein receptors crucial to skeletal development. That same year, researchers discovered that one of the receptor genes--when mutated--somehow leads to dwarfism.

Suddenly, Naski had his work cut out for him. "The question burning in the field was, Just how do these mutations affect receptor function?" said Naski, an HHMI physician postdoctoral fellow at Washington University School of Medicine in St. Louis. "It was an easy question to dive into." Now, Naski has begun to find answers. In the June, 1996, issue of Nature Genetics , he and colleagues reported that several mutations can jumpstart a protein receptor that inhibits bone growth. The receptor is called fibroblast growth receptor (FGF) 3.

When mutated, FGF receptor 3 can cause bones to simply stop growing. Depending on the mutation, an individual with a faulty FGF receptor 3 gene may die shortly after birth or endure a range of problemsfrom abnormal curvature of the spine to arthritisthat accompany dwarfism.

Normally, longitudinal bonessuch as those in our arms and legsgrow with the guidance of cartilage cells. Found at the end of bones, these cells weave a cartilage-based matrix into which bones extend. Like a paint-by-numbers set, cartilage cells shape an outline that bone fills in. The FGF receptor 3 sits quietly on cartilage cells until activated by a protein called fibroblast growth factor (FGF). When signalled, the receptor stops the matrix-forming cartilage cells in their tracks. Researchers are uncertain just how this process works.

What Naski did was examine three known mutations in the FGF receptor 3 gene that causes this bone-growing process to go awry. The first mutationresulting from a single nucleotide alteration in the FGF receptor 3 genecauses the most common form of dwarfism, known as achondroplasia. The other mutations each cause a more severe type of dwarfism called thanatophoric dysplasia. In the lab, Naski nurtured three sets of cultured cells, each engineered to contain one of the mutations. He left out FGF, the protein normally needed to activate the receptor. Naski then looked for signs of FGF receptor 3 activity in the cells. And he found it. Even without FGF present, these mutated cells began multiplying and undergoing chemical reactions. Essentially, the mutated FGF receptor 3 was always operating.

Some of the mutations exerted a stronger effect on the receptor than others. Cells carrying the receptor for thanatophoric dysplasia mutations were the most active, Naski said. These cells behaved as though they were totally `on.' By comparison, the achondroplasia-causing mutations produced a partially active receptor. Naski thinks the difference may explain why thanatophoric dysplasia is more physically devastating than achondroplasia. In the future, Naski's findings may help researchers begin looking for ways to repair the mutated FGF receptor 3 gene. That could eventually lead to diagnosisor even treatmentof dwarfism and its complications.