DEFECTIVE SPLICING OF MESSENGER-RNA FROM ONE COL1A1 ALLELE OF TYPE-I COLLAGEN IN NONDEFORMING (TYPE-I) OSTEOGENESIS IMPERFECTA

Osteogenesis imperfecta (OI) type I is the mildest form of heritable b one fragility resulting from mutations within the COL1A1 gene. We stud ied fibroblasts established from a child with OI type I and demonstrat ed underproduction of alpha1 (I) collagen chains and alpha1 (I) mRNA. Indirect RNase protection suggested two species of alpha1 (I) mRNA, on e of which was not collinear with fully spliced alpha1 (I) mRNA. The n oncollinear population was confined to the nuclear compartment of the cell, and contained the entire sequence of intron 26 and a G --> A tra nsition in the first position of the intron donor site. The G --> A tr ansition was also identified in the genomic DNA. The retained intron c ontained an in-frame stop codon and introduced an out-of-frame inserti on within the collagen mRNA producing stop codons downstream of the in sertion. These changes probably account for the failure of the mutant RNA to appear in the cytoplasm. Unlike other splice site mutations wit hin collagen mRNA that resulted in exon skipping and a truncated but i n-frame RNA transcript, this mutation did not result in production of a defective collagen proalpha1 (I) chain. Instead, the mild nature of the disease in this case reflects failure to process the defective mRN A and thus the absence of a protein product from the mutant allele.