Osteogenesis imperfecta. The position of substitution for glycine by cysteine in the triple helical domain of the pro alpha 1(I) chains of type I collagen determines the clinical phenotype.

Starman, Barbra J.; Eyre, David R.; Charbonneau, Harry; Harrylock, Maria; Weis, Mary Ann; Weiss, L.; Graham, J M; Byers, Peter H.

doi:10.1172/jci114286

Cited by 72 publications

(36 citation statements)

References 36 publications

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“…Various investigators have reported on the dental status of OI patients with glycine mutations in this region of the collagen type I triple helix and none of the nine patients mentioned in these reports had clear clinical evidence of dentinogenesis imperfecta. [14][15][16][17][18] The mechanistic link between collagen type I mutations and dentinogenesis imperfecta has not been elucidated in any detail. Our data nevertheless show that patients sharing the same mutation had a high concordance for the condition.…”

Section: Resultsmentioning

confidence: 99%

Genotype–phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I

et al. 2010

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Osteogenesis imperfecta (OI) is a heritable disorder with bone fragility that is often associated with short stature, tooth abnormalities (dentinogenesis imperfecta), and blue sclera. The most common mutations associated with OI result from the substitution for glycine by another amino acid in the triple helical domain of either the a1 or the a2 chain of collagen type I. In this study, we compared the results of genotype analysis and clinical examination in 161 OI patients (median age: 13 years) who had glycine mutations in the triple helical domain of a1(I) (n¼67) or a2(I) (n¼94). Serine substitutions were the most frequently encountered type of mutation in both chains. Compared with patients with serine substitutions in a2(I) (n¼40), patients with serine substitutions in a1(I) (n¼42) on average were shorter (median height z-score À6.0 vs À3.4; P¼0.005), indicating that a1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the a2(I) chain but not in the a1(I) chain. Patients with mutations affecting the first 120 amino acids at the amino-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta. Among patients from different families sharing the same mutation, about 90 and 75% were concordant for dentinogenesis imperfecta and blue sclera, respectively. These data should be useful to predict disease phenotype in newly diagnosed OI patients.

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Section: Resultsmentioning

confidence: 99%

Genotype–phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I

et al. 2010

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“…Although the nature of mutations responsible for OI type I is largely unknown, structural alterations (5) and point mutations in (54,55) or near the triple helical coding region (56-58) appear to be rare causes. Mutations that could alter the apparent expression of COL IA I and lead to decreased type I collagen synthesis include deletion of one allele or structural rearrangements that create a nonfunctional allele, promoter and enhancer mutations, splicing mutations, small deletions and insertions that create a shift in the reading frame ofthe protein, and single nucleotide substitutions that result in premature termination codons.…”

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confidence: 99%

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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“…Mutations in the a2(I) chain are less easily detected. First position cysteine mutations in the a 1(I) chain resulting in mild OI have been reported at al(I) amino acid 94 (29) and a (I) 175 (30). Cysteine mutations have also been found in severe 01 type III at al(I) 415 (29), 526 (29), and in the lethal 01 type II at al(I) 988 (27), 748 (31), 904 (32), and 718 (29).…”

Section: Discussionmentioning

confidence: 99%

“…First position cysteine mutations in the a 1(I) chain resulting in mild OI have been reported at al(I) amino acid 94 (29) and a (I) 175 (30). Cysteine mutations have also been found in severe 01 type III at al(I) 415 (29), 526 (29), and in the lethal 01 type II at al(I) 988 (27), 748 (31), 904 (32), and 718 (29). In contrast to the mild disease with a COOH-terminal a2(I) serine for glycine substitution described by Spotila et al (25) these cases appear to support the postulate of more severe disease with a COOHterminal mutation.…”

Section: Discussionmentioning

confidence: 99%

An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro alpha 1(I) chain of type I collagen.

Shapiro¹,

Stover²,

Burn³

et al. 1992

J. Clin. Invest.

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Mutations affecting the proal(I) or proa2(I) collagen genes have been identified in each of the major clinical types of osteogenesis imperfecta. This study reports the presence of a heritable connective tissue disorder in a family with an osteopenic syndrome which has features of mild osteogenesis imperfecta but was considered idiopathic osteoporosis in the proband. At age 38, while still premenopausal, she was found to have osteopenia, short stature, hypermobile joints, mild hyperelastic skin, mild scoliosis, and blue sclerae. There was no history of vertebral or appendicular fracture. Hip and vertebral bone mineral density measurements were consistent with marked fracture risk. Delayed reduction SDS-PAGE of pepsin-digested collagens from dermal fibroblast cultures demonstrated an anomalous band migrating between al(I) and al(III). This band merged with the normal a-chains upon prereduction, indicating an unexpected cysteine residue. Cyanogen bromide peptide mapping suggested that the mutation was in the smaller NH2-terminal peptides. cDNA was reverse transcribed from mRNA and amplified by the polymerase chain reaction. A basepair mismatch between proband and control al(I) cDNA hybrids was detected by chemical cleavage with hydroxylamine:piperidine. The cysteine substitution was thus localized to al(I) exon 9 within the cyanogen bromide 4 peptide. Nucleotide sequence analysis localized a G -* T point mutation in the first position of helical codon 43, replacing the expected glycine (GGT) residue with a cysteine (TGT). The prevalence of similar NH2-terminal mutations in subjects with this phenotype which clinically overlaps idiopathic osteoporosis remains to be determined. (J. Clin. Invest. 1992.

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Osteogenesis imperfecta. The position of substitution for glycine by cysteine in the triple helical domain of the pro alpha 1(I) chains of type I collagen determines the clinical phenotype.

Abstract: Skin fibroblasts grown from three individuals with osteogenesis imperfecta (OI)

Cited by 72 publications

References 36 publications

Genotype–phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I

Genotype–phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen 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.

An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro alpha 1(I) chain of type I collagen.

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