An infant was born with
osteogenesis imperfecta (OI) and died after 7 days. In addition, there were amniotic constriction bands and
amputations of several digits of the upper and lower limbs. The radiologic picture was suggestive of type III OI. Histomorphometric analysis of the bone showed a trabecular bone volume of 15.1% compared to 26.9% for age-matched controls. This was due to a decreased apposition of matrix by the osteoblasts. Because abnormal
collagen synthesis has been suggested as the underlying defect in most forms of OI,
collagen studies were undertaken using intact tissues. Bone and skin
collagen solubilities were strikingly reduced. Shortened
type I collagen molecules, representing 25% of the total
type I collagen, were produced by
pepsin digestion of the demineralized bone matrix. The molecular weight of the shortened
collagen, was 10 kd lower than normal for both the alpha 1 and alpha 2 chains as determined by gel electrophoresis. The bone
acetic acid-soluble
collagen showed few shortened alpha-chains. Twenty-five percent of the
acid-soluble bone
collagen was cleaved into shortened molecules by a
pepsin digestion. The shortened alpha 1 chain was purified by high-performance liquid chromatography (HPLC) and digested with CNBr. The analysis of the resulting fragments by HPLC and by gel electrophoresis unequivocally demonstrated that the shortened alpha 1 chain was derived from the alpha 1(I) chains and that the
pepsin sensitivity extends from the amino terminal end of the chain to the alpha 1(I) CB5
peptide, approximately 120 residues inside the triple helix. These studies show a distinct structural abnormality of
type I collagen in the bone matrix of this patient resulting in an increased sensitivity of the
collagen to general enzymatic proteolysis. The importance of correlating clinical and biochemical information in OI is emphasized; classification and genetic counseling based only on clinical observations are inaccurate.