Substitutions for glycine alpha 1-637 and glycine alpha 2-694 of type I procollagen in lethal osteogenesis imperfecta. The conformational strain on the triple helix introduced by a glycine substitution can be transmitted along the helix

Type I collagen alpha 1(I) glycine to serine substitutions, resulting from G-to-A mutations, were defined in three cases of osteogenesis imperfecta (OI). The Gly substitutions displayed a gradient of phenotypic severity according to the location of the mutation in the collagen triple helix. The most C-terminal of these, Gly565 to Ser, led to the lethal perinatal (type II) form of OI, whereas the more N-terminal mutations, Gly415 and Gly352 to Ser, led to severe OI (type III/IV) and moderate OI (type IVB) respectively. These data support the notion that glycine substitutions towards the C-terminus of the alpha 1(I) or alpha 2(I) chains will be more clinically severe than those towards the N-terminus. This results from the more disruptive effect of the mutations at the C-terminus on helix initiation and C- and N-terminal helix directional propagation. This generalization must be modified by considering the nature of the glycine substitution and the surrounding amino acid sequence, since the helix is composed of subdomains of differing stability which will affect the ability of helix re-nucleation and propagation.

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Substitution of serine for glycine 883 in the triple helix of the pro alpha 1 (I) chain of type I procollagen produces osteogenesis imperfecta type IV and introduces a structural change in the triple helix that does not alter cleavage of the molecule by procollagen N-proteinase.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)43820-3 ◽

1994 ◽

Vol 269 (48) ◽

pp. 30352-30357

Author(s):

S J Lightfoot ◽

M S Atkinson ◽

G Murphy ◽

P H Byers ◽

K E Kadler

Keyword(s):

Structural Change ◽

Osteogenesis Imperfecta ◽

Triple Helix ◽

Type I ◽

Osteogenesis Imperfecta Type ◽

Type I Procollagen ◽

Type Iv

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A point mutation in a type I procollagen gene converts glycine 748 of the alpha 1 chain to cysteine and destabilizes the triple helix in a lethal variant of osteogenesis imperfecta.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)47857-x ◽

1987 ◽

Vol 262 (30) ◽

pp. 14737-14744 ◽

Cited By ~ 13

Author(s):

B E Vogel ◽

R R Minor ◽

M Freund ◽

D J Prockop

Keyword(s):

Osteogenesis Imperfecta ◽

Point Mutation ◽

Triple Helix ◽

Type I ◽

Type I Procollagen

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Substitution of cysteine for glycine-α1-691 in the proα1(I) chain of type I procollagen in a proband with lethal osteogenesis imperfecta destabilizes the triple helix at a site C-terminal to the substitution

Biochemical Journal ◽

10.1042/bj2790747 ◽

1991 ◽

Vol 279 (3) ◽

pp. 747-752 ◽

Cited By ~ 9

Author(s):

B Steinmann ◽

A Westerhausen ◽

C D Constantinou ◽

A Superti-Furga ◽

D J Prockop

Keyword(s):

Thermal Stability ◽

Osteogenesis Imperfecta ◽

Triple Helix ◽

Cysteine Residue ◽

Special Importance ◽

Type I ◽

Type I Procollagen ◽

Genomic Dnas ◽

Local Unfolding ◽

A Site

Skin fibroblasts from a proband with lethal osteogenesis imperfecta synthesized a type I procollagen containing a cysteine residue in the alpha 1(I) helical domain. Assay of thermal stability of the triple helix by proteinase digestion demonstrated a decreased temperature for thermal unfolding of the protein. Of special importance was the observation that assays of thermal stability by proteinase digestion revealed two bands present in a 2:1 ratio of about 140 and 70 kDa; the 140 kDa band was reducible to a 70 kDa band. Further analysis of the fragments demonstrated that the cysteine mutation produced a local unfolding of the triple helix around residue 700 and apparently exposed the arginine residue at position 704 in both the alpha 1(I) and alpha 2(I) chains. Analysis of cDNAs and genomic DNAs demonstrated a single-base mutation that changed the GGT codon for glycine-691 of the alpha 1(I) chain to a TGT codon for cysteine. The mutation was not found in DNA from either of the proband's parents. Since the proteinase assay of helical stability generated a fragment of 700 residues that retained disulphide-bonded cysteine residues at alpha 1-691, the results provide one of the first indications that glycine substitutions in type I procollagen can alter the conformation of the triple helix at a site that is C-terminal to the site of the substitution.

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Substitutions of aspartic acid for glycine-220 and of arginine for glycine-664 in the triple helix of the pro α1(I) chain of type I procollagen produce lethal osteogenesis imperfecta and disrupt the ability of collagen fibrils to incorporate crystalline hydroxyapatite

Biochemical Journal ◽

10.1042/bj3110815 ◽

1995 ◽

Vol 311 (3) ◽

pp. 815-820 ◽

Cited By ~ 16

Author(s):

A A Culbert ◽

M P Lowe ◽

M Atkinson ◽

P H Byers ◽

G A Wallis ◽

...

Keyword(s):

Osteogenesis Imperfecta ◽

Aspartic Acid ◽

Triple Helix ◽

Type I Collagen ◽

Collagen Fibrils ◽

Morphological Data ◽

Type I ◽

Type Ii ◽

Col1a1 Gene ◽

Type I Procollagen

We identified two infants with lethal (type II) osteogenesis imperfecta (OI) who were heterozygous for mutations in the COL1A1 gene that resulted in substitutions of aspartic acid for glycine at position 220 and arginine for glycine at position 664 in the product of one COL1A1 allele in each individual. In normal age- and site-matched bone, approximately 70% (by number) of the collagen fibrils were encrusted with plate-like crystallites of hydroxyapatite. In contrast, approximately 5% (by number) of the collagen fibrils in the probands' bone contained crystallites. In contrast with normal bone, the c-axes of hydroxyapatite crystallites were sometimes poorly aligned with the long axis of fibrils obtained from OI bone. Chemical analysis showed that the OI samples contained normal amounts of calcium. The probands' bone samples contained type I collagen, overmodified type I collagen and elevated levels of type III and V collagens. On the basis of biochemical and morphological data, the fibrils in the OI samples were co-polymers of normal and mutant collagen. The results are consistent with a model of fibril mineralization in which the presence of abnormal type I collagen prevents normal collagen in the same fibril from incorporating hydroxyapatite crystallites.

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