2.1. Winchester syndrome

At least one mutation in the MMP14 gene has been found to cause Winchester syndrome, a rare inherited bone disease that is characterized by a loss of bone tissue (osteolysis), particularly in the hands and feet, as well as joint and skin abnormalities. The mutation changes a single protein building block (amino acid) in matrix metallopeptidase 14. Specifically, it replaces the amino acid threonine with the amino acid arginine at position 17 (written as Thr17Arg or T17R).

The identified mutation alters matrix metallopeptidase 14 so that less of the enzyme is able to reach the cell surface. As a result, not enough of the enzyme is available to break down components of the extracellular matrix and activate matrix metallopeptidase 2. It is unclear how a shortage of this enzyme leads to the signs and symptoms of Winchester syndrome. It is possible that a loss of matrix metallopeptidase 2 activation somehow disrupts the balance of new bone creation and the breakdown of existing bone during bone remodeling, causing a progressive loss of bone tissue. How a reduced amount of matrix metallopeptidase 14 leads to the other features of Winchester syndrome is unknown.