Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Scientific Background

OI or brittle bone disease (frequency 1 in 10,000) is a clinically and genetically heterogeneous group of diseases characterized by increased brittleness of the bones. Apart from some very rare special types, inheritance is autosomal dominant. Mutations causing the disease are detected in the genes COL1A1 and COL1A2 in approx. 90% of all cases. Frequently, they lead to substitution of glycine in the triple helical domain of the type I collagen. The severity of the clinical signs and symptoms depends on the affected gene as wells as type and location of the mutation (genotype-phenotype correlation). The rare forms of OI, usually of autosomal recessive inheritance, are frequently characterized by certain clinical features. According to international guidelines, the analysis of these genes is currently recommended only after profound clinical evaluation.

OI is categorized into the following types:

1. Autosomal dominant forms (frequent)

Type I (most frequent form, approx. 65% of all cases) is characterized by a mild course with moderate brittleness (10-20 broken bones before puberty), blue sclerae and post-pubertal hearing loss in 50% of all affected patients. Tinnitus, aortic insufficiency and thin skin (in approx. 20% of all cases) are characteristic. There is a distinction between type IA with and type IB without dentinogenesis imperfecta.

Type II (approx. 20% of all cases) is the most severe form and is usually intrauterine or within the first few weeks postnatally lethal. Sporadic cases are frequently caused by germline mosaicism; the recurrence risk in following pregnancies is approx. 10%.

Type III (approx. 5% of all cases) has an especially varying phenotype. Extreme short stature, skeletal deformities, approx. 100 bone fractures before puberty and hearing loss are typical. Soft bones, scoliosis and dentinogenesis imperfecta are characteristic as well.

Type IV (approx. 10% of all cases) is a mild form characterized by short stature and moderate skeletal deformities; no coloring of the sclerae and moderate brittleness of the bones. Subtype A and B with or without dentinogenesis imperfecta are distinguished.

The disease is caused by mutations in the type I collagen genes COL1A1 (2/3 of all cases) and COL1A2 (1/3 of all cases). These mutations cause a reduced synthesis of pro-collagen α1, α2 or a structural change of collagen. The phenotypical heterogeneity is probably caused by the impact of modifier genes and by structural differences. In total, approximately 1,000 mutations have been discribed, 60% of which affect the amino acid glycine.

Type V is described as a rare form of unknown cause with hypertrophic calluses formation, mesh-like histology of the bones, dense epiphyses, skeletal deformities and varying degree of brittleness.

2. Autosomal recessive form (rare)

Type VI is described as a very rare, moderately severe form of OI, characterized by skeletal deformities and variable brittleness of the bones. Histological examinations show lamellae with fish-bone appearence. Recently, mutations in the FKBP10 gene, which encodes the chaperone FKBP65, were detected in a small number of Turkish families. FKBP65 is involved in the folding of type I collagen.

Type VII (2-3% of all lethal OI cases) is characterized by multiple bone fractures, extremely low mineralization and “popcorn epiphyses”. The cause is mutations in the CRTAP gene. CRTAP encodes a component of the collagen 3-hydroxylation complex (post translational prolyl 3-hydroxylation of collagen type I and II). The complex modifies Pro986 of the α1(I) chain. This facilitates the folding and stabilizes the chain. Absence of Pro986 hydroxylation leads to a prolonged folding of the collagen helix and to its over-modification (28-43% increase of hydroxylation of lysine residue). Since type II collagen in the cartilage is modified by prolyl 3-hydroxylation as well, the epiphyses are also affected.

Type VIII (rare, mainly occurring among Irish emigrants and in Western Africa, where 1% of the population are carriers and type VIII is occurring with the same frequency as OI type II) is characterized by white sclera, a short, barrel-shaped thorax, long hands and extremely under-mineralized bones. It is caused by mutations in the prolyl 3-hydroxylase gene LEPRE1, which modifies Pro986 of the α1(I) (post-translational prolyl 3-hydroxilation of collagen type I and II). Mutations have a structural effect and clinical signs and symptoms are similar to OI type VII.

Type IX (rare) is a moderately severe form of OI without rhizomelia. It is caused by mutations in the PPIB gene. PPIB encodes a peptidyl-prolyl cis-trans isomerase that catalyzes the prolyl isomerization and is essential for the folding of type I collagen.