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chapter 25
RNA and Protein Synthesis
1. Aberration in the control mechanisms that alter the
balance between synthesis and degradation. This
imbalance can lead either to excessive deposition or
depletion of collagen.
2. Synthesis of structurally altered collagen due to
defects at the level of DNA transcription, RNA
processing, translation, or posttranslational
modifications.
3. Imbalance in the relative rates of synthesis of
genetically distinct collagens.
4. Abnormalities in the packing of collagen molecules
into a fiber or in the interaction of collagen fibers with
other extracellular components of the connective
tissue.
are examples of secondary collagen diseases. The mecha-
nisms that lead to collagen diseases are:
Transcription and Translation of
Collagen Polypeptides
In general, the transcription and translation of collagen
polypeptides resemble other proteins. The primary RNA
transcript is capped and polyadenylated, introns are re-
moved, and the functional mRNA is transported to the
cytoplasm. The procollagen mRNA, in addition to being
one of the largest mRNAs in eukaryotic cells, contains
unusually high amounts of G and C, because these bases
are overrepresented in the codons for glycine and proline.
As is the case for other secretory proteins, the procollagen
mRNA encodes a signal sequence coding for hydrophobic
amino acids at the amino terminal ends. The signal se-
quences of proa
1
chain are different from the proa
2
chain
and are unusually long
( 1 0 0
amino acid residues) in com-
parison with other secreted proteins (15-30 residues). Be-
cause of their hydrophobicity, these signal sequences are
thought to facilitate binding and transport of the nascent
polypeptide into cisternae of the endoplasmic reticulum.
The signal sequences are removed by proteolysis within
the membrane during the translation. The synthetic rate of
proa chain is rather slow and is probably related to the un-
folding of the secondary structure of procollagen mRNA,
which is rich in GC content.
Molecular defects at the levels of transcription and
translation of collagen polypeptides have not yet been
clearly established but may cause one type of
Ehlers-
Danlos syndrome (type IV).
This disorder is characterized
by decreased synthesis of type III collagen in the aorta,
intestinal tract, skin, and probably other tissues. Among
the Ehlers-Danlos disorders, type IV is the most severe
because of the threat of arterial rupture or gastrointesti-
nal perforation. Ehlers-Danlos syndrome is a group of
inherited disorders that share similar clinical symptoms;
many have been attributed to specific errors in the struc-
ture or metabolism of collagen (Table 25-5). The major
phenotypic features of Ehlers-Danlos syndrome include
hyperextensible skin, hypermobile joints, easy bruisabil-
ity, and friability of tissues. The clinical severity of these
disorders is highly variable. Defects in splicing, tran-
scription, or translation may also cause
osteogenesis im-
perfecta.
In this disease, fibroblasts or tissue samples
have a markedly diminished capacity for type I collagen
TABLE 25-5
Ehlers-Danlos Syndrome
Type
Inheritance
Biochemical Defect
Collagen Fib ril Diameter
I
AD
Unknown
Increased
II
AD
Unknown
Increased
III
AD
Unknown
Increased
IV
ADorAR
Decreased type III collagen synthesis and its intracellular accumulation
Heterogeneous
V
XL
Unknown
Heterogeneous
XL
Unknown
Increased
VI
AR
Lysyl hydroxylase deficiency
Decreased
VII
AD
Deletion of exons from the genes of proa,(I) and p ro a
2
(I) that encode
Heterogeneous
the amino-terminal cleavage site; required for the action of
procollagen aminoprotease
VII
AD
Unknown
Not determined
IX
SL
Lysyl oxidase deficiency
Increased
X
AR
Fibronectin deficiency
Not determined
AD=Autosomal dominant; AR=autosomal recessive; XL=X-linked.
