High Proportion of Mutant Osteoblasts Is Compatible with Normal Skeletal Function in Mosaic Carriers of Osteogenesis Imperfecta**Presented as a platform presentation at the National Meeting of the American Society of Bone and Mineral Research (Late-Breaking Research Session), San Antonio, TX, September 2002.

Abstract

Individuals with mosaicism for the autosomal dominant bone dysplasia osteogenesis imperfecta (OI) are generally identified by having more than one affected child. The mosaic carriers have both normal and mutant cell populations in somatic and germline tissues but are unaffected or minimally affected by the type I collagen mutation that manifests clinically in their heterozygous offspring. We determined the proportion of mutant osteoblasts in skeletal tissue of two mosaic carriers who each have a COL1A1 mutation in a high proportion of dermal fibroblasts. Both carriers had normal height and bone histology; the first carrier had normal lumbar spine measurements (L1-L4), as determined by dual-energy x-ray absorptiometry (Z = +1.17). In cultured cells from the first carrier, studied by labeled PCR and single-cell PCR over successive passages, the collagen mutation was present in 85% of fibroblasts and 50% and 75% of osteoblasts from her right iliac crest and left patella, respectively, with minimal selection. The second carrier was studied by PCR amplification of DNA from autopsy paraffin blocks. The proportion of heterozygous cells was 40% in calvarium, 65% in tracheal ring, and 70% in aorta. Thus, in OI, substantially normal skeletal growth, density, and histology are compatible with a 40%-75% burden of osteoblasts heterozygous for a COL1A1 mutation. These data are encouraging for mesenchymal stem-cell transplantation, since mosaic carriers are a naturally occurring model for cell therapy.

Asymptomatic parental mosaicism for osteogenesis imperfecta associated with a new splice site mutation in COL1A2

“…Altered bone microstructure and bone geometry, evaluated by HR‐pQCT, has been reported in patients with OI types I, III, and IV 28, 29. However, in two mosaic carriers, normal skeletal growth, bone density, and bone histology were found in spite of 40–75% burden of osteoblasts heterozygous for a COL1A1 mutation 30, which is concordant with our findings.…”

Local transplantation is an effective method for cell delivery in the osteogenesis imperfecta murine model

“…The selective advantage of wild type cells over cells bearing a mutation has been observed in studies of patients that are mosaic for OI mutations. The presence of 40% normal cells minimizes the effects from the mutant population, preventing the appearance of the clinical phenotype [20]. These data indicate that transplantation procedures would be successful even with partial engraftment of normal MSCs.…”

New perspectives on osteogenesis imperfecta

“…Mosaic carrier parents have barely detectable phenotypes, even with high burdens of mutant osteoblasts 200 . Cellular therapy recapitulates the mosaic situation by infusing normal mesenchymal stem cells (MSCs), with osteoblast differentiation potential, into affected individuals.…”