Diminished type I collagen synthesis and reduced alpha 1(I) collagen messenger RNA in cultured fibroblasts from patients with dominantly inherited (type I) osteogenesis imperfecta.

Rowe, David W.; Shapiro, Jay R.; Poirier, Miriam C.; Schlesinger, Sandra

doi:10.1172/jci112012

Cited by 104 publications

(42 citation statements)

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“…Dermal fibroblasts from these individuals synthesized proa 1(I) and proa2(I) chains in a 1:1 ratio instead of the expected 2:1 ratio. Additional analyses by Rowe et al (7) and Genovese and Rowe (8) and by our laboratory (Willing, M. C., and P. H. Byers, unpublished observations) indicate that the decreased proa I(I) production reflects a reduction in steady-state COLlA1 mRNA levels. These data, taken together suggest that 01 type I frequently results from mutations that affect the apparent expression of COLlA 1, but the mechanisms by which expression is altered are not clear.…”

mentioning

confidence: 64%

Frameshift mutation near the 3' end of the COL1A1 gene of type I collagen predicts an elongated Pro alpha 1(I) chain and results in osteogenesis imperfecta type I.

Willing

Cohn²,

Byers³

1990

J. Clin. Invest.

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Osteogenesis imperfecta (01) is a heterogeneous disorder of type I collagen of which OI type I, an autosomal dominant condition, is the mildest and most common form. Affected individuals have blue sclerae, normal stature, bone fragility without significant deformity and osteopenia. Fibroblasts from most affected individuals produce about half the expected amount of structurally normal type I collagen as a result of decreased synthesis of one of its constituent chains, proal(I), but the nature of the mutations which result in 01 type I are unknown. We describe a three generation family with OI type I in which all affected members have one normal COLlA1 allele and another from which the intragenic Eco RI restriction site near the 3' end of the gene is missing. Amplification by polymerase chain reaction and sequence determination of the normal allele and of the mutant allele in the domain that normally contains the Eco RI site demonstrated a 5-bp deletion frop the mutant allele. The deletion changes the translational readingframe beginning at the Eco RI site and predicts the synthesis of a proal(I) chain that extends 84 amino acids beyond the normal termination. Although the mutant proal(I) chain is synthesized in an in vitro translation system, we are unable to detect its presence in intact cells, suggesting that it is unstable and rapidly destroyed in one of the cell's degradative pathways. Our analysis of individuals with 01 type I from 20 families indicates that this is a unique mutation and suggests that the phenotype can result from multiple mechanisms that decrease the synthesis of normal type I procollagen molecules, including those that alter protein stability. (J. Clin. Invest. 1990. 85:282-290.) common form, 01 type I, is characterized by normal or near normal stature, bone fragility without significant deformity, osteopenia, blue sclerae, and inheritance in an autosomal dominant fashion (1). Adult onset hearing loss and/or dentinogenesis imperfecta are seen in some kindreds. Family studies have demonstrated linkage of the 01 type I phenotype to restriction fragment length polymorphisms in COLlA1, the gene encoding the proal(I) chain of type I collagen, in the majority of cases, and to sites in COLlA2, the gene encoding the proa2(I) chain of type I collagen, in the minority (2-4).Little is known about the nature ofthe mutations that result in 01 type I, except that dermal fibroblasts from affected individuals produce and efficiently secrete about half the expected amount of structurally normal type I collagen (4, 5). The abnormality in type I collagen production is reflected in altered ratios of type I to type III collagen in skin (4), and represents the most characteristic biochemical correlate ofthe phenotype. Barsh et al. (6) demonstrated that the disturbance in type I collagen production is due to decreased synthesis of proal(I) chains in the patients they studied. Dermal fibroblasts from these individuals synthesized proa 1(I) and proa2(I) chains in a 1:1 ratio instead of the expected 2...

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mentioning

confidence: 64%

Frameshift mutation near the 3' end of the COL1A1 gene of type I collagen predicts an elongated Pro alpha 1(I) chain and results in osteogenesis imperfecta type I.

Willing

Cohn²,

Byers³

1990

J. Clin. Invest.

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“…Although there are a large number (Ͼ50) of exons in COL1A1 and COL1A2 genes, single exon deletions are a rare finding (52). Some mutations lead to the functional loss of the affected allele, which has been suggested to cause mild (type I) forms of OI (53). Mutations in the collagen genes of the severely affected patients are thought to lead both to a reduced type I collagen synthesis, secretion, and deposition of structurally abnormal collagen molecules into the matrix (39,54,55).…”

Section: Resultsmentioning

confidence: 99%

Age-related Changes in Human Bone Proteoglycan Structure

Grzesik

Frazier

Shapiro

et al. 2002

Journal of Biological Chemistry

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Proteoglycans (PGs) are a family of molecules that undergo extensive post-translational modifications that include addition of glycosaminoglycan (GAG) chains as well as N-and O-linked oligosaccharides to the protein core. PG composition and structure have been reported to alter with age. To test whether the post-translational modifications to PGs can serve as in vitro surrogate end point markers for chronological age, the extent of GAG modifications was determined for PGs derived from normal human bone cells of 14 donors (age range, fetal to 60 years). Isolated cells were steady state radiolabeled with 35 SO 4 2؊ and [ 3 H]GlcN. For biglycan and decorin, iduronate content was linearly correlated with age (increased 1.5؋ between fetal and age 60 years). For the syndecan-like heparan sulfate PG, the N-sulfation of post-natal cells increased over 3.5-fold until reaching a plateau during the 4th decade of life. The amount of O-linked oligosaccharides was also found to decrease as a function of increasing normal donor age, whereas the specific activity of the metabolic precursor pool remained constant regardless of donor age. These age-related changes in post-translational modifications were then used to demonstrate that osteoblasts derived from patients with osteogenesis imperfecta did not exhibit facets of a pre-mature aging, but rather were arrested in a fetallike phenotypic state. A growth matrix rich in thrombospondin altered PG metabolism in osteoblastic cells, resulting in the production and secretion of the fetal-like (rich in O-linked oligosaccharides) forms of decorin and biglycan. This effect was qualitatively different from the effect of transforming growth factor-␤, which predominantly altered GAGs rather than O-linked oligosaccharides. No other Arg-Gly-Asp protein (fibronectin, vitronectin, type I collagen, osteopontin, and bone sialoprotein) showed any detectable effect on PG metabolism in bone cells. These results indicate that a proper matrix stoichiometry is critical for metabolism of PGs.

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“…A fibroblast strain was derived from a skin explant taken from the inner aspect of the upper arm. Fibroblasts were maintained as previously described ( 12). Confluent cultures were harvested for protein or RNA after 48 h in fresh culture media supplemented daily with 25 ,ug/ml ascorbic acid.…”

Section: Methodsmentioning

confidence: 99%

“…The synthesis ofproa 1 ( 1 ) collagen chains ( 11 ) and the steady-state level of a 1(I) mRNA appears to be reduced by -50% (12,13), suggesting that one of the two COLlA 1 alleles is "null. "…”

Section: Introductionmentioning

confidence: 99%

Defective splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming (type I) osteogenesis imperfecta.

et al. 1993

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Osteogenesis imperfecta (OI) type I is the mildest form of heritable bone fragility resulting from mutations within the COLlAl gene. We studied fibroblasts established from a child with 01 type I and demonstrated underproduction of al (I) collagen chains and al (I) mRNA. Indirect RNase protection suggested two species of al (I) mRNA, one of which was not collinear with fully spliced al (I) mRNA. The noncollinear population was confined to the nuclear compartment of the cell, and contained the entire sequence of intron 26 and a G -* A transition in the first position of the intron donor site. The G --A transition was also identified in the genomic DNA. The retained intron contained an in-frame stop codon and introduced an out-of-frame insertion within the collagen mRNA producing stop codons downstream of the insertion. These changes probably account for the failure of the mutant RNA to appear in the cytoplasm. Unlike other splice site mutations within collagen mRNA that resulted in exon skipping and a truncated but inframe RNA transcript, this mutation did not result in production of a defective collagen proal (I) chain. Instead, the mild nature of the disease in this case reflects failure to process the defective mRNA and thus the absence ofa protein product from the mutant allele. (J. Clin. Invest.

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Diminished type I collagen synthesis and reduced alpha 1(I) collagen messenger RNA in cultured fibroblasts from patients with dominantly inherited (type I) osteogenesis imperfecta.

Cited by 104 publications

References 38 publications

Frameshift mutation near the 3' end of the COL1A1 gene of type I collagen predicts an elongated Pro alpha 1(I) chain and results in osteogenesis imperfecta type I.

Frameshift mutation near the 3' end of the COL1A1 gene of type I collagen predicts an elongated Pro alpha 1(I) chain and results in osteogenesis imperfecta type I.

Age-related Changes in Human Bone Proteoglycan Structure

Defective splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming (type I) osteogenesis imperfecta.

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