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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.
J Clin Invest. 1990 Jan; 85(1):282-90.JCI

Abstract

Osteogenesis imperfecta (OI) 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, pro alpha 1(I), but the nature of the mutations which result in OI type I are unknown. We describe a three generation family with OI type I in which all affected members have one normal COL1A1 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 from the mutant allele. The deletion changes the translational reading-frame beginning at the Eco RI site and predicts the synthesis of a pro alpha 1(I) chain that extends 84 amino acids beyond the normal termination. Although the mutant pro alpha 1(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 OI 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.

Authors+Show Affiliations

Department of Pediatrics, University of Washington, Seattle 98195.No affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

2295701

Citation

Willing, M C., et al. "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." The Journal of Clinical Investigation, vol. 85, no. 1, 1990, pp. 282-90.
Willing MC, Cohn DH, Byers PH. 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. J Clin Invest. 1990;85(1):282-90.
Willing, M. C., Cohn, D. H., & Byers, P. H. (1990). 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. The Journal of Clinical Investigation, 85(1), 282-90.
Willing MC, Cohn DH, Byers PH. 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. J Clin Invest. 1990;85(1):282-90. PubMed PMID: 2295701.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Willing,M C, AU - Cohn,D H, AU - Byers,P H, PY - 1990/1/1/pubmed PY - 1990/1/1/medline PY - 1990/1/1/entrez SP - 282 EP - 90 JF - The Journal of clinical investigation JO - J Clin Invest VL - 85 IS - 1 N2 - Osteogenesis imperfecta (OI) 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, pro alpha 1(I), but the nature of the mutations which result in OI type I are unknown. We describe a three generation family with OI type I in which all affected members have one normal COL1A1 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 from the mutant allele. The deletion changes the translational reading-frame beginning at the Eco RI site and predicts the synthesis of a pro alpha 1(I) chain that extends 84 amino acids beyond the normal termination. Although the mutant pro alpha 1(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 OI 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. SN - 0021-9738 UR - https://www.unboundmedicine.com/medline/citation/2295701/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_ L2 - https://doi.org/10.1172/JCI114424 DB - PRIME DP - Unbound Medicine ER -