Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta

Am J Hum Genet. 2010 Mar 12;86(3):389-98. doi: 10.1016/j.ajhg.2010.01.034. Epub 2010 Feb 25.


Osteogenesis imperfecta (OI) is characterized by bone fragility and fractures that may be accompanied by bone deformity, dentinogenesis imperfecta, short stature, and shortened life span. About 90% of individuals with OI have dominant mutations in the type I collagen genes COL1A1 and COL1A2. Recessive forms of OI resulting from mutations in collagen-modifying enzymes and chaperones CRTAP, LEPRE1, PPIB, and FKBP10 have recently been identified. We have identified an autosomal-recessive missense mutation (c.233T>C, p.Leu78Pro) in SERPINH1, which encodes the collagen chaperone-like protein HSP47, that leads to a severe OI phenotype. The mutation results in degradation of the endoplasmic reticulum resident HSP47 via the proteasome. Type I procollagen accumulates in the Golgi of fibroblasts from the affected individual and a population of the secreted type I procollagen is protease sensitive. These findings suggest that HSP47 monitors the integrity of the triple helix of type I procollagen at the ER/cis-Golgi boundary and, when absent, the rate of transit from the ER to the Golgi is increased and helical structure is compromised. The normal 3-hydroxylation of the prolyl residue at position 986 of the triple helical domain of proalpha1(I) chains places the role of HSP47 downstream from the CRTAP/P3H1/CyPB complex that is involved in prolyl 3-hydroxylation. Identification of this mutation in SERPINH1 gives further insight into critical steps of the collagen biosynthetic pathway and the molecular pathogenesis of OI.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Base Sequence
  • Child, Preschool
  • Collagen Type I / chemistry
  • Collagen Type I / metabolism
  • Consanguinity
  • Conserved Sequence
  • DNA / genetics
  • Endoplasmic Reticulum / metabolism
  • Fatal Outcome
  • Female
  • Genes, Recessive
  • HSP47 Heat-Shock Proteins / genetics*
  • HSP47 Heat-Shock Proteins / metabolism
  • Homozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Osteogenesis Imperfecta / diagnostic imaging
  • Osteogenesis Imperfecta / genetics*
  • Osteogenesis Imperfecta / metabolism
  • Pedigree
  • Phenotype
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Stability
  • Radiography
  • Sequence Homology, Amino Acid


  • Collagen Type I
  • HSP47 Heat-Shock Proteins
  • SERPINH1 protein, human
  • DNA
  • Proteasome Endopeptidase Complex