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COL1A1 C-propeptide mutations cause ER mislocalization of procollagen and impair C-terminal procollagen processing.

ABSTRACT: Mutations in the type I procollagen C-propeptide occur in ~6.5% of Osteogenesis Imperfecta (OI) patients. They are of special interest because this region of procollagen is involved in ? chain selection and folding, but is processed prior to fibril assembly and is absent in mature collagen fibrils in tissue. We investigated the consequences of seven COL1A1 C-propeptide mutations for collagen biochemistry in comparison to three probands with classical glycine substitutions in the collagen helix near the C-propeptide and a normal control. Procollagens with C-propeptide defects showed the expected delayed chain incorporation, slow folding and overmodification. Immunofluorescence microscopy indicated that procollagen with C-propeptide defects was mislocalized to the ER lumen, in contrast to the ER membrane localization of normal procollagen and procollagen with helical substitutions. Notably, pericellular processing of procollagen with C-propeptide mutations was defective, with accumulation of pC-collagen and/or reduced production of mature collagen. In vitro cleavage assays with BMP-1?±?PCPE-1 confirmed impaired C-propeptide processing of procollagens containing mutant pro?1(I) chains. Overmodified collagens were incorporated into the matrix in culture. Dermal fibrils showed alterations in average diameter and diameter variability and bone fibrils were disorganized. Altered ER-localization and reduced pericellular processing of defective C-propeptides are expected to contribute to abnormal osteoblast differentiation and matrix function, respectively.

SUBMITTER: Barnes AM

PROVIDER: S-EPMC7521940 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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COL1A1 C-propeptide mutations cause ER mislocalization of procollagen and impair C-terminal procollagen processing.

Barnes Aileen M AM Ashok Aarthi A Makareeva Elena N EN Brusel Marina M Cabral Wayne A WA Weis MaryAnn M Moali Catherine C Bettler Emmanuel E Eyre David R DR Cassella John P JP Leikin Sergey S Hulmes David J S DJS Kessler Efrat E Marini Joan C JC

Biochimica et biophysica acta. Molecular basis of disease 20190502 9

Mutations in the type I procollagen C-propeptide occur in ~6.5% of Osteogenesis Imperfecta (OI) patients. They are of special interest because this region of procollagen is involved in α chain selection and folding, but is processed prior to fibril assembly and is absent in mature collagen fibrils in tissue. We investigated the consequences of seven COL1A1 C-propeptide mutations for collagen biochemistry in comparison to three probands with classical glycine substitutions in the collagen helix n ...[more]

PMID: 31055083

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Project description:BACKGROUND:Data have shown that healthy children and adolescents have an inadequate intake of zinc, an essential nutrient for growth. It is unclear whether zinc supplementation can enhance bone health during this rapid period of growth and development. OBJECTIVE:The primary aim of this study was to determine the effect of zinc supplementation on biochemical markers of bone turnover and growth in girls entering the early stages of puberty. The secondary aim was to test moderation by race, body mass index (BMI) classification, and plasma zinc status at baseline. METHODS:One hundred forty seven girls aged 9-11 y (46% black) were randomly assigned to a daily oral zinc tablet (9 mg elemental zinc; n = 75) or an identical placebo (n = 72) for 4 wk. Fasting plasma zinc, procollagen type 1 amino-terminal propeptide (P1NP; a bone formation marker), carboxy-terminal telopeptide region of type 1 collagen (ICTP; a bone resorption marker), and insulin-like growth factor I (IGF-I) were assessed at baseline and post-test. Additional markers of bone formation (osteocalcin) and resorption (urinary pyridinoline and deoxypyridinoline) were also measured. RESULTS:Four weeks of zinc supplementation increased plasma zinc concentrations compared with placebo [mean change, 1.8 ?mol/L (95% CI: 1.0, 2.6) compared with 0.2 ?mol/L (95% CI: -0.3, 0.7); P < 0.01]. Zinc supplementation also increased serum P1NP concentrations compared with placebo [mean change, 23.8 ?mol/L (95% CI: -14.9, 62.5) compared with -31.0 ?mol/L (95% CI: -66.4, 4.2); P = 0.04). There was no effect from zinc supplementation on osteocalcin, ICTP, pyridinoline, deoxypyridinoline, or IGF-I. There was no moderation by race, BMI classification, or plasma zinc status at baseline. CONCLUSIONS:Our data suggest that 4 wk of zinc supplementation increases bone formation in premenarcheal girls. Further studies are needed to determine whether supplemental zinc can improve childhood bone strength. This trial was registered at clinicaltrials.gov as NCT01892098.

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COL1A1 C-propeptide mutations cause ER mislocalization of procollagen and impair C-terminal procollagen processing.

Publications

COL1A1 C-propeptide mutations cause ER mislocalization of procollagen and impair C-terminal procollagen processing.

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