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

Aileen M. Barnes, Aarthi Ashok, Elena N. Makareeva, Marina Brusel, Wayne A. Cabral, Mary Ann Weis, Catherine Moali, Emmanuel Bettler, David R. Eyre, John P. Cassella, Sergey Leikin, David J.S. Hulmes, E. Kessler, Joan C. Marini*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 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 proα1(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.

Original languageEnglish
Pages (from-to)2210-2223
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number9
StatePublished - 1 Sep 2019


FundersFunder number
National Institutes of HealthAR037318, AR036794
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Child Health and Human DevelopmentZIAHD000256
University of Washington
Eunice Kennedy Shriver National Institute of Child Health and Human Development
European CommissionNMP2-CT-2003-504017
Israel Science Foundation1360/07


    • BMP-1
    • C-propeptide
    • Collagen processing
    • Endoplasmic reticulum localization
    • Osteogenesis imperfecta


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