Osteogenesis imperfecta (Osteogenesis imperfecta) - Genes COL1A1, COL1A2, and LEPRE1 CRTAP.            

Osteogenesis imperfecta (OI) is a group of genetic disorders affecting mainly bones. There are eight recognized forms of osteogenesis imperfecta, designated from type I to type VIII. Types can be distinguished by its signs and symptoms, although their features overlap. Type I is the mildest form of the disease and type II is the most severe.

Milder forms of the disease, including type I, are characterized by bone fractures during childhood and adolescence that often are caused by mild trauma. Fractures occur less frequently in adulthood. People with milder forms of the disease usually have a blue tint or gray sclera, and may develop hearing loss in adulthood. The most serious types of the disease can cause frequent bone fractures may begin before birth and are caused by a slight, or even no apparent cause trauma. Additional features of these alterations may include blue sclera, short stature, hearing loss, respiratory problems, and dentinogenesis imperfecta. The most severe forms of osteogenesis imperfecta, especially Type II may include an abnormally small ribcage fragile and underdeveloped lungs. Newborns with these anomalies have life - threatening breathing problems and often die shortly after birth.

This process is due to mutations in the COL1A1, COL1A2, CRTAP and LEPRE1. Mutations in the COL1A1 genes, located on the long arm of chromosome 17 (17q21.33) in the gene and COL1A2, located on the long arm of chromosome 7 (7q22.1) are responsible for over 90 percent of all cases of osteogenesis imperfecta. These genes encode proteins used to form collagen type I. This type of collagen is the most abundant protein in bone, skin and other connective tissues that provide structure and strength to the body. Have identified more than 400 mutations in the COL1A1 gene and about 300 COL1A2 gene mutations cause osteogenesis imperfecta. These genetic changes reduce the amount of type I collagen produced in the body or results in the production of abnormal versions, making bones fragile and easily broken.

The CRTAP gene, located on the short arm of chromosome 3 (3p22.3), encoding the protein associated with cartilage which plays an important role in normal bone development. This protein is related to two other proteins, Leprecan and cyclophilin B as part of a complex that helps process certain forms of collagen. They have identified at least 5 mutations in the CRTAP gene responsible for a rare type of osteogenesis imperfecta that is usually classified as Type VII. Mutations in this gene prevent or reduce the production of cartilage - associated protein. Without this protein, bone and other connective tissues do not form properly, resulting in a very severe form of the disease.

The LEPRE1 gene, located on the short arm of chromosome 1 (1p34.1), encoding the enzyme Leprecan or prolil3-hydroxylase-1. This enzyme acts with two other proteins, cartilage associated protein and cyclophilin B as part of a complex processing aid for normal collagen folding and assembly. It may also be important for the release of collagen molecules in the extracellular matrix. Additionally, it is thought that Leprecan can act as a tumor suppressor, preventing cells from growing and dividing too rapidly or uncontrollably. They have identified at least four mutations in the gene causing LEPRE1 osteogenesis imperfecta type VIII. These mutations prevent the cells from producing any functional Leprecan. Without this enzyme, altered collagen molecules are folded incorrectly. These defects weaken the connective tissue collagen, resulting in an extremely slow growing and fragile, thin bones that can fracture before birth.

In cases of the disease without mutations identified in the COL1A1, COL1A2, or LEPRE1 CRTAP gene, the cause of the disorder is unknown. These cases include osteogenesis imperfecta types V and VI.

Most cases of OI have a pattern of autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to cause the alteration. Many people with type I or IV inherited a mutation from a parent who has the disease. Most children with more severe forms of osteogenesis imperfecta (such as type II and type III) have no history of the disease in his family. In these children, the condition is caused by sporadic mutations in COL1A1 or COL1A2 gene the.

Less often, osteogenesis imperfecta has an autosomal recessive inheritance pattern, which means that 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. Some cases of osteogenesis imperfecta type III are autosomal recessive. These cases usually result from mutations in genes COL1A2 and COL1A1 different. When osteogenesis imperfecta is caused by mutations in the gene CRTAP or LEPRE1, the condition also has an autosomal recessive inheritance pattern.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with osteogenesis imperfecta, by complete PCR amplification of the exons of the COL1A1, COL1A2, and LEPRE1 CRTAP respectively genes 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).