MSc (Biochemie), North-West University, Potchefstroom CampusBIOSYNTHESIS OF AN ABNORMAL TYPE I PROCOLLAGEN
IN A FAMILY WITH OSTEOGENESIS IMPERFECTA
(Original title: Biosintese van 'n afwykende vorm van
tipe I prokollageen in 'n familie met
osteogenesis imperfecta).
Osteogenesis imperfecta (01) is a heterogeneous group of
heritable disorders of connective tissue which are characterized by increased fragility of bone and are frequently
associated with other clinical features, such as skeletal
deformities, blue sclerae, hearing impairment and dentinogenesis imperfecta. 01 can be divided into at least four
different subtypes : type I, type II, type III and type IV.
A variety of observations, made on cultured skin fibroblasts,
showed that some forms of the heritable disorders of
connective tissues involve changes in the metabolism of
type I procollagen.
Synthesis of procollagen was examined in skin fibroblasts
from a patient with type IOI. Treatment of the procollagen with pepsin, followed by SOS-PAGE, revealed the presence of type I collagen in which two al (I) chains were
linked through interchain disulfide bonds. Fragmentation
of the disulfide bonded al (I) dimers with vertebrate
collagenase and cyanogen bromide,demonstrated the presence
of a cysteine residue in al (I)CBS, a fragment containing
amino acid residues 124 - 402 of the a l (I) collagen chain.
The presence of one mutant pro a l (I) chain in trimers of
type I procollagen was found to reduce the thermal stability
of the protein with 2,5~ C. In contrast , the presence of
two mutant proal(I) chains was found to reduce the thermal
stability of type I procollagen with 1掳c. Three kinds of
type I trimers were therefore formed: a normal type with
normal proa l(I) chains; a type I trimer with one normal and
one mutant proa l(I) chain and a type I trimer with two mutant
proal(I) chains. Type I trimers containing one mutant
proa l (I) chain were secreted at a slower rate than normal .
A fraction of 63% was secreted in the fast phase of secretion
as opposed to the normal fraction of 96 %. The presence
of the mutant proa l(I) chains in type I trimers had 路no
adverse effect on processing by N-proteinase. The most
likely explanation for these disruptive changes in the
physical stability and secretion of the mutant procollagen
is that a cysteine res i due is substituted for a glycine
in half of the proa l(I) chains synthesized by the patient's
fibroblasts.
Radiolo gica l examination of the proband and seven other
family members, representing three generations of a large
pedigree , revealed a large variation in phenotype . Analysis
of the collagen from fibroblasts of less and more severely
affected members, all showed the presence of the cysteine
containing proal( I ) chains.Master
