An intronic deletion leading to skipping of exon 21 of COL1A2 in a boy with mild osteogenesis imperfecta.

A mild form of osteogenesis imperfecta was diagnosed in a 5-year-old boy with short stature, osteoporosis, blueish sclerae, dentinogenesis imperfecta, hyperextensible joints and bruisable skin. His skin fibroblasts synthesized both normal and shortened pro-alpha 2(I) collagen chains. Procollagen I molecules containing the shortened pro-alpha 2 chains were unstable and thus virtually excluded from secretion at 37 degrees C. Secretion was only partially restored at 30 degrees C. Cyanogen bromide mapping confined the defect to peptide alpha 2(I)CB4. PCR amplification of cDNA showed that the 108 nucleotides corresponding to exon 21 (coding for residues 274 to 309 of the helical domain) were missing in about half of the COL1A2 mRNA. Genomic DNA analysis showed that both exons 21 of COL1A2 were intact, but nucleotides +2 to +40 in intron 21 were deleted on one allele. The intronic deletion altered the conserved nucleotides at position +2 and +5 of the splicing donor site and apparently caused skipping of exon 21 during mRNA splicing. The mild phenotype associated with this COL1A2 mutation may be explained by very poor secretion of the structurally defective procollagen I molecules, which minimizes their deleterious effects on extracellular matrix formation.