A lethal variant of osteogenesis imperfecta has a single base mutation that substitutes cysteine for glycine 904 of the alpha 1(I) chain of type I procollagen. The asymptomatic mother has an unidentified mutation producing an overmodified and unstable type I procollagen.
J Clin Invest
; 83(2): 574-84, 1989 Feb.
Article
em En
| MEDLINE
| ID: mdl-2913053
ABSTRACT
A fraction of the pro alpha 1(I) and pro alpha 2(I) chains in type I procollagen synthesized by the fibroblasts from a proband with a lethal variant of osteogenesis imperfecta were overmodified by posttranslational reactions. After digestion with pepsin, some of the alpha 1(I) chains were recovered as disulfide-linked dimers. Mapping of cyanogen bromide peptides indicated that the disulfide link was contained in alpha 1-CB6, the cyanogen bromide fragment containing amino acid residues 823-1014 of the alpha 1(I) chain. Nucleotide sequencing of cDNA clones demonstrated a substitution of T for G that converted glycine 904 of the alpha 1(I) chain to cysteine. A large fraction of the type I procollagen synthesized by the proband's fibroblasts had a thermostability that was 3-4 degrees C lower than the normal type I procollagen as assayed by brief proteinase digestion. In addition, the type I procollagen synthesized by the proband's fibroblasts was secreted with an abnormal kinetic pattern in that there was a lag period of about 30 min in pulse-chase experiments. The mutation of glycine to cysteine was not found in type I procollagen synthesized by fibroblasts from the proband's parents. Therefore, the mutation was a sporadic one. However, the mother's fibroblasts synthesized a type I procollagen in which part of the pro alpha chains were overmodified and had a lower thermostability. Therefore, the proband may have inherited a mutated allele for type I procollagen from her mother that contributed to the lethal phenotype. The mother was asymptomatic. She was somewhat short and had slightly blue sclerae but no definitive signs of a connective tissue abnormality. The observations on the mother indicated, therefore, that a mutation that causes synthesis of a type I procollagen with a lowered thermal stability does not necessarily produce a heritable disorder of connective tissue.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteogênese Imperfeita
/
Pró-Colágeno
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Cisteína
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Morte Fetal
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Genes Letais
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Glicina
Limite:
Female
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Humans
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Newborn
/
Pregnancy
Idioma:
En
Ano de publicação:
1989
Tipo de documento:
Article