The CSTB gene provides instructions for making a protein called cystatin B. This protein reduces the activity of (inhibits) enzymes called cathepsins. Cathepsins help break down certain proteins in the lysosomes (compartments in the cell that digest and recycle materials). While the specific function of cystatin B is unclear, it may help protect the cells' proteins from cathepsins that leak out of the lysosomes.
One region of the CSTB gene has a particular repeating sequence of 12 DNA building blocks (nucleotides) written as CCCCG-CCCCG-CG. This sequence, called a dodecamer repeat, is usually repeated two or three times within a part of the gene that helps regulate cystatin B protein production.
In almost all affected individuals, Unverricht-Lundborg disease is caused by an increased number of copies (expansion) of the dodecamer repeat in the CSTB gene. Most people with this disorder have more than 30 repeats of the dodecamer sequence in both copies of the CSTB gene.
In a small number of individuals, one copy of the CSTB gene has the expanded dodecamer repeat while the second copy carries one of nine other identified mutations. Some of these mutations substitute one protein building block (amino acid) for another amino acid in the cystatin B protein. Others result in a shortened protein that may function improperly or not at all, or cause the protein to be pieced together incorrectly. Only one individual with Unverricht-Lundborg disease has been reported to have mutations other than the dodecamer repeat expansion in both copies of the gene in each cell.
The expanded dodecamer repeat in the CSTB gene seems to interfere with the production of cystatin B protein. Levels of cystatin B in affected individuals are only 5 to 10 percent of normal, and cathepsin levels are significantly increased. These changes are believed to cause the signs and symptoms of Unverricht-Lundborg disease, but the specific mechanism is unknown.
- cystatin B (stefin B)
- liver thiol proteinase inhibitor
- stefin B