Bruck type 1 syndrome - FKBP10 gene
Syndrome type 1 Bruck is characterized by the association of osteogenesis imperfecta and congenital joint contractures. Signs and symptoms of the disease include osteoporosis and bone fragility, wormian bones (additional bone pieces between the skull sutures), scoliosis due to spinal deformities, short stature and progressive joint contractures (sometimes associated with pterygium) that often affect knees, ankles and elbows.
This process is due to mutations in the FKBP10 gene, located on the long arm of chromosome 17 (17q21.2). This gene encodes the binding protein FK506-65 (FKBP65), located in the endoplasmic reticulum. The FKBP65 protein is important for correct processing of collagen and elastin, which are part of the intricate network of proteins and other molecules that form in the extracellular matrix. This matrix provides structure and strength to connective tissues that support joints and internal organs. In the extracellular matrix, collagen molecules are crosslinked together to form long thin fibrils. The crosslinking results in very strong collagen fibers. The FKBP65 protein binds to collagen molecules and plays a role in crosslinking. It thought to be involved in the hydroxylation reaction that modifies a particular region of the collagen molecule and is necessary for crosslinking of the molecules. The FKBP65 protein is also involved in the formation of elastin. In particular, FKBP65 contributes to proper folding of tropoelastin. Multiple copies of tropoelastin adhere to each other to make elastin. Elastin is the major component of elastic fibers, which provide strength and elasticity to connective tissues as part of the extracellular matrix.
Mutations identified in the FKBP10 gene coding lead to little or no protein FKBP65. Consequently, collagen crosslinking is severely affected, resulting in an extracellular matrix with very few collagen fibrils and with little disorganized network. It is unclear how these changes in collagen lead to signs and symptoms of Bruck syndrome 1. In addition, it is unknown whether abnormalities in elastin are also involved in the development of this disease. In addition, it is not clear why some people with mutations in the gene FKBP10 have joint deformities, as well as brittle bones and some not.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI perform detection of mutations associated with type 1 Bruck syndrome 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).