Kuskokwim syndrome ... (Kuskokwim syndrome) - Gen FKBP10
Kuskokwim syndrome is characterized by joint deformities due to contractures, which restrict the movement of the affected joints. This alteration has only been found in a population of native Alaskan Yup'ik Eskimos known as, living in and around a region of southwestern Alaska known as the Kuskokwim River Delta.
Kuskokwim syndrome, the most common contractures affect knees, ankles and elbows, although other joints, especially of the lower part of the body may be affected. Contractures are usually present at birth and during infancy worsen. Then they tend to stabilize after childhood and maintained throughout life. Some people with this condition have some bone abnormalities most frequently affecting the spine, pelvis and feet. Affected individuals may develop lordosis, scoliosis, wedge - shaped vertebrae, clavicle or clubbed. In addition, people affected are often lower than their peers and may have macrocephaly.
The Kuskokwim syndrome is due to alterations in the sequence of FKBP10 gene, located on the long arm of chromosome 17 (17q21.2). This gene, encoding FKBP65, important for the proper processing of collagen molecules, which give structure and strength to connective tissues that support the bones, joints , and body organs protein. In the extracellular matrix, collagen molecules are linked together to form long thin fibrils. The crosslinking results in the formation of strong collagen fibrils. The FKBP10 protein binds to collagen molecules and plays a role in the links. It is believed to participate in a reaction called hydroxylation amending a particular region of the collagen molecule and is necessary for the bonds of the molecules. The FKBP10 protein is also involved in the formation of elastin. In particular, FKBP10 help correct folding of tropoelastin protein. Multiple copies of tropoelastin adhere to each other to form elastin. Elastin is the major component of elastic fibers, which provide strength and elasticity to the connective tissues, as part of the extracellular matrix.
It has identified at least one mutation in the FKBP10 gene responsible Kuskokwim syndrome. This mutation Tyr293del, eliminates the amino acid tyrosine at position 293 of the protein, leading to the synthesis of an unstable protein which is easily broken. As a result, people with Kuskokwim syndrome have only about 5 percent of the normal amount of protein FKBP65. Although the mechanism is not clear, reducing the FKBP10 protein causes a decrease in the hydroxylation of collagen, which affects the collagen cross - linking and network causes disorganized collagen molecules. It is unclear how these changes in the collagen matrix are involved in the development of joint contractures and other abnormalities in people with Kuskokwim syndrome.
Kuskokwim syndrome is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell have mutations. The parents of an individual with an autosomal recessive disorder each have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with syndrome Kuskokwim by complete PCR amplification of the exons of the FKBP10 gene, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).