FKBP10 gene

At least one mutation in the FKBP10 gene causes Kuskokwim syndrome, a rare condition that affects a small number of people from the Yup'ik Eskimo population in southwest Alaska. This condition is characterized by joint deformities called contractures, particularly in the knees, ankles, and elbows. The contractures restrict the movement of affected joints.

The FKBP10 gene mutation involved in Kuskokwim syndrome deletes a single protein building block (amino acid) from the FKBP10 protein. The mutation, written as Tyr293del, removes the amino acid tyrosine at position 293. This genetic change leads to production of a protein that is unstable and easily broken down. As a result, people with Kuskokwim syndrome have only about 5 percent of the normal amount of FKBP10 protein. Although the mechanism is unclear, the reduction of FKBP10 protein leads to a severe decrease in collagen hydroxylation, which interferes with collagen cross-linking. The network of collagen molecules in affected individuals is disorganized. It is unclear how changes in the collagen matrix are involved in the development of joint contractures in people with Kuskokwim syndrome. It is unknown whether elastin abnormalities also contribute to the features of this disorder.

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Mutations in the FKBP10 gene are also associated with another connective tissue disorder known as Bruck syndrome 1. This condition has features similar to both osteogenesis imperfecta type XI and Kuskokwim syndrome (described above): affected individuals have fragile bones as well as joint contractures that typically affect the knees, ankles, and elbows.

The mutations that cause Bruck syndrome 1 lead to the production of little to no FKBP10 protein. While people with Kuskokwim syndrome have some residual collagen hydroxylation, it is nearly absent in people with osteogenesis imperfecta type XI and Bruck syndrome 1. As a result, collagen cross-linking is severely impaired: there are very few collagen fibrils in the extracellular matrix, and the network is sparse and disorganized. How these changes in collagen lead to the signs and symptoms of osteogenesis imperfecta type XI and Bruck syndrome 1 is unclear. In addition, it is unknown whether abnormalities in elastin are also involved in development of these conditions. Researchers are unsure why some people with these more severe gene mutations have joint deformities in addition to fragile bones and others do not.