Thirty-three novel COL1A1 and COL1A2 mutations in patients with osteogenesis imperfecta types I-IV

Ward, Leanne M.; Lalic, Liljana; Roughley, Peter J.; Glorieux, Francis H.

doi:10.1002/humu.1124

Cited by 44 publications

(34 citation statements)

References 18 publications

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“…The repetitive sequence of exon 44 has made it a hot spot for single triplet deletions and duplications. Nine of the 11 known triplet deletions or duplications in ␣1(I) (11)(12)(13)(14) have occurred in this region.…”

Section: Discussionmentioning

confidence: 99%

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Type I Collagen Triplet Duplication Mutation in Lethal Osteogenesis Imperfecta Shifts Register of α Chains throughout the Helix and Disrupts Incorporation of Mutant Helices into Fibrils and Extracellular Matrix

Cabral

Mertts

Makareeva

et al. 2003

Journal of Biological Chemistry

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The majority of collagen mutations causing osteogenesis imperfecta (OI) are glycine substitutions that disrupt formation of the triple helix. A rare type of collagen mutation consists of a duplication or deletion of one or two Gly-X-Y triplets. These mutations shift the register of collagen chains with respect to each other in the helix but do not interrupt the triplet sequence, yet they have severe clinical consequences. We investigated the effect of shifting the register of the collagen helix by a single Gly-X-Y triplet on collagen assembly, stability, and incorporation into fibrils and matrix. These studies utilized a triplet duplication in COL1A1 exon 44 that occurred in the cDNA and gDNA of two siblings with lethal OI. The normal allele encodes three identical Gly-AlaHyp triplets at aa 868 -876, whereas the mutant allele encodes four. The register shift delays helix formation, causing overmodification. Differential scanning calorimetry yielded a decrease in T m of 2°C for helices with one mutant chain and a 6°C decrease in helices with two mutant chains. An in vitro binary co-processing assay of N-proteinase cleavage demonstrated that procollagen with the triplet duplication has slower N-propeptide cleavage than in normal controls or procollagen with pro␣1(I) G832S, G898S, or G997S substitutions, showing that the register shift persists through the entire helix. The register shift disrupts incorporation of mutant collagen into fibrils and matrix. Proband fibrils formed inefficiently in vitro and contained only normal helices and helices with a single mutant chain. Helices with two mutant chains and a significant portion of helices with one mutant chain did not form fibrils. In matrix deposited by proband fibroblasts, mutant chains were abundant in the immaturely cross-linked fraction but constituted a minor fraction of maturely cross-linked chains. The profound effects of shifting the collagen triplet register on chain interactions in the helix and on fibril formation correlate with the severe clinical consequences.

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Section: Discussionmentioning

confidence: 99%

“…Only 10 cases of single triplet deletion or duplication have been reported (11)(12)(13)(14), including five deletions and three duplications in the ␣1(I) chain and 2 deletions in the ␣2(I) chain. There are also four cases involving deletion or duplication of two triplets, all in the ␣2(I) chain (14,15).…”

mentioning

confidence: 99%

Type I Collagen Triplet Duplication Mutation in Lethal Osteogenesis Imperfecta Shifts Register of α Chains throughout the Helix and Disrupts Incorporation of Mutant Helices into Fibrils and Extracellular Matrix

Cabral

Mertts

Makareeva

et al. 2003

Journal of Biological Chemistry

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“…The clinical heterogeneity was reflected by a variety of mutations in the COL1A1 and COL1A2 genes that are thought to be the underlying cause of most cases of OI (4). Recently, a new group of patients have been defined in terms of clinical severity and by the exclusion of type I collagen gene mutations (5,6). The lack of a clear relationship between collagen mutation and phenotype as well as the absence of type I collagen mutations in the recently defined groups has suggested the involvement of other modifying factors.…”

Section: Osteogenesis Imperfecta (Oi)mentioning

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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“…Although there have been several reports on the spectra of COL1A1 and COL1A2 mutations in Lithuanian, Finnish, American, Israeli, and Canadian populations (Benusiene and Kucinskas, 2003;Hartikka, et al, 2004;Pepin, et al, 1997;Ries-Levavi, et al, 2004;Ward, et al, 2001), they have been restricted to Western populations and only a few cases have been reported from Asia. The expression profiles and characteristics of mutations are known to be influenced by ethnic background.…”

Section: Introductionmentioning

confidence: 99%

Mutational spectrum of type I collagen genes in Korean patients with osteogenesis imperfecta

et al. 2006

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Mutations in the type I collagen genes COL1A1 and COL1A2 are responsible for the dominantly inherited connective tissue disorder osteogenesis imperfecta (OI). The severity of OI is diverse, ranging from perinatal lethality to a very mild phenotype that is characterized by normal stature and the absence of deformities. Although there have been several studies on the mutational spectra of COL1A1 and/or COL1A2 in Western populations, very few cases have been reported from Asia. In this study, we investigated 67 unrelated Korean probands with OI and used nucleotide sequence analysis to detect COL1A1 and COL1A2 mutations. Thirty-five different mutations were identified in the two genes, including 24 novel mutations. Among the 35 kinds of detected mutations, 15 were glycine substitutions (seven in COL1A1 and eight in COL1A2), one was a nonsense mutation, four were frameshift mutations in COL1A1, three were in-frame duplications in COL1A2, and 12 were splice site mutations (seven in COL1A1 and five in COL1A2). Until now, mutations in the COL1A1 and COL1A2 genes known to cause OI were unique and rarely repeated in other families. Interestingly, the c.982G>A (p.Gly328Ser) mutation in COL1A2 was found recurrently and was the causative mutation in five independent OI probands. Haplotype analysis of the COL1A2 gene revealed that four probands from five independent OI probands with c.982G>A (p.Gly328Ser) had a common haplotype. Our clinical data showed the heterogeneity even within a specific genotype, which suggested the complex expression of this disease.

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Thirty-three novel COL1A1 and COL1A2 mutations in patients with osteogenesis imperfecta types I-IV

Cited by 44 publications

References 18 publications

Type I Collagen Triplet Duplication Mutation in Lethal Osteogenesis Imperfecta Shifts Register of α Chains throughout the Helix and Disrupts Incorporation of Mutant Helices into Fibrils and Extracellular Matrix

Type I Collagen Triplet Duplication Mutation in Lethal Osteogenesis Imperfecta Shifts Register of α Chains throughout the Helix and Disrupts Incorporation of Mutant Helices into Fibrils and Extracellular Matrix

Age-related Changes in Human Bone Proteoglycan Structure

Mutational spectrum of type I collagen genes in Korean patients with osteogenesis imperfecta

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