title: Somatic cell mosaicism: another source of phenotypic heterogeneity in nuclear families with osteogenesis imperfecta.
abstract: Mutations in the genes coding for the pro alpha 1 and pro alpha 2 chains of type I procollagen have been found in many patients with osteogenesis imperfecta (OI), a heritable disorder of connective tissue. The severity of the disease varies between families and even among members of the same family. This phenotypic variability covers a spectrum extending from very mild forms that cannot be easily detected to perinatally lethal forms. One explanation for this phenotypic variability is the nature of the mutation in the type I procollagen genes. Another explanation is mosaicism. Here we report on 2 families with propositi who have OI, whereas their mothers had a milder form of the disease. In one family, the molecular defect was previously shown to be a substitution of alpha 1(904) by cysteine [Constantinou et al., 1990]. The biochemical phenotype was characterized by significant post-translational overmodification of the mutated type 1 collagen molecules which also had a 3-4 degrees C decrease in their thermal unfolding. Also, secretion of the procollagen into the culture media was delayed. In the second family, the proposita's muscle fibroblasts synthesized and secreted type I procollagen molecules that were highly over-modified along the entire length of their triple-helical domain. Cells from the mother also synthesized normal and over-modified protein, although the amount of over-modified protein was less than that synthesized by her daughter's cells. The exact molecular defect has not yet been defined.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Biochemistry and Molecular Biology, Jefferson Institute of Molecular Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: C D
authors.initials: CD
authors.lastname: Constantinou-Deltas
authors.forename: R L
authors.initials: RL
authors.lastname: Ladda
authors.forename: D J
authors.initials: DJ
authors.lastname: Prockop
mesh_terms: D000328:Adult; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype