A mutation of the gene for cartilage-associated protein may lead to a recessive and lethal form of osteogenesis imperfecta, according to Dr. Joan C. Marini of the National Institute of Child Health and Human Development in Bethesda, Md.
“We identified a recessive form of lethal osteogenesis imperfecta, caused by null mutations in [cartilage-associated protein] CRTAP, a gene that encodes a protein that is essential for one of the posttranslational modifications of types I and II collagen,” Dr. Marini and her colleagues reported.
While mutations in type I collagen lead to most cases of osteogenesis imperfecta (OI), researchers in the field had sought a recessive form of the disease. The authors screened dermal fibroblasts from 10 children with lethal (type II), or very severe (type III) OI who had type I collagen with excess posttranslational modification of the alpha chain helical region but a normal primary structure, using a fibroblast cell line from newborn foreskin as a control. They also evaluated 11 patients who had severe OI without the excess modification described above and without a collagen defect, 6 normal control subjects, and 1 control patient with classic (type III) OI. The authors used polymerase-chain-reaction (PCR) assays to amplify DNA sequences in the subjects' genomes. They used reverse-transcriptase PCR assays to determine CRTAP mRNA levels.
After sampling mRNA from the fibroblasts of 10 children with type II or III OI who had excess posttranslational modification but lacked a collagen mutation, they determined that 3 infants had CRTAP mRNA levels that were 0%–25% of the normal range. In addition to low levels of CRTAP mRNA, the infants had defects in both CRTAP alleles, they lacked CRTAP protein, and they had minimal hydroxylation of type I collagen. All of these infants died within the first year of life. Fibroblasts from the parents of two of these three infants (one set of parents did not participate in the analysis) had normal CRTAP mRNA levels, a finding that suggests that the infants had more than one defective allele. As in all children with lethal OI, those with the recessive form of the disease have severely undermineralized bones that result in multiple prenatal fractures. Those children with the recessive mutation also have a small head circumference, proptosis, and white or light blue sclerae (N. Engl. J. Med. 2006;355:2757–64).
Defects in the CRTAP gene are likely to cause 2%–3% of all cases of lethal OI.