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Met>Val substitution in a highly conserved region of the pro-α1(I) collagen C-propeptide domain causes alternative splicing and a mild EDS/OI phenotype
  1. S Symoens1,
  2. L Nuytinck2,
  3. E Legius3,
  4. F Malfait1,
  5. P J Coucke1,
  6. A De Paepe1
  1. 1Centre for Medical Genetics, University Hospital Ghent, B-9000 Ghent, Belgium
  2. 2Innogenetics, B-9000 Ghent, Belgium
  3. 3Centre for Human Genetics, K.U. Leuven, B-3000 Leuven, Belgium
  1. Correspondence to:
 A De Paepe
 Centre for Medical Genetics, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium; Anne.DePaepeUGent.be

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Type I procollagen is a fibrillar collagen consisting of two pro-α1(I) chains and one pro-α2(I) chain. This procollagen heterotrimer contains a central triple helical domain that is flanked by amino- and carboxy-terminal propeptides (N- and C-propeptides), which are cleaved off after assembly and secretion. The C-propeptides, involved in the formation of post-translational disulphide bonds, are responsible for the correct alignment of the three individual procollagen chains and direct chain–chain recognition.

Mutations in the genes coding for type I procollagen (COL1A1 and COL1A2) have been found in osteogenesis imperfecta (OI) and in the arthrochalasis type of Ehlers-Danlos syndrome (previously EDS types VIIA and B). The heritable brittle bone disease osteogenesis imperfecta has a broad clinical spectrum, ranging from mild to lethal forms.1 The mildest form, type I OI, is usually caused by mutations generating a premature termination codon and leading to COL1A1 haploinsufficiency. All the procollagen type I that is formed is structurally normal, but its amount is decreased. The more severe forms, types III and IV OI, and the lethal type II OI are generally caused by mutations affecting the structure of type I procollagen. The most common mutations are missense mutations which substitute a crucial glycine residue, occurring in every third position of the triple helix, for a bulkier amino acid. The other mutations are in-frame single exon deletions, splicing defects, and small in-frame insertions and deletions.

In addition to the more than 200 type I procollagen mutations identified in OI, a limited number of mutations in these genes have been reported in EDS. The arthrochalasis type of EDS is caused by mutations leading to the skipping of exon 6 in either the pro-α1 or the pro-α2 chain of procollagen type I.2 Missplicing or skipping of this exon results in the removal of the cleavage site for …

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