RECURRENCE OF OSTEOGENESIS IMPERFECTA BECAUSE OF PATERNAL MOSAICISM - GLY(862)-]SER SUBSTITUTION IN A TYPE-I COLLAGEN GENE (COL1A1)

We determined that two siblings with type III osteogenesis imperfecta (OI) had the same single base substitution that converted the codon for glycine (Gly) 862 to a codon for serine (Ser) in exon 44 of the al chain of the type I (alpha 1(I)) collagen gene (COL1A1). The mutation was also detected in various paternal tissues; the mutant allele accounted for approximately 11% of the COL1A1 alleles in blood, 24% of those in fibroblasts, and 43% of those in sperm determined by allele-specific colony hybridization using amplified genomic sequences. These findings demonstrate that germ-line mosaicism in the phenotypically normal father is responsible for the recurrence. There is a cluster of serine substitutions for Gly (Gly(832), Gly(844) and Gly(901)) which is associated with nonlethal phenotypes and which is located between two lethal clusters. In the cases studied here, a Gly(862)-->Ser mutation was identified that is located inside the nonlethal cluster.