Recurrence of osteogenesis imperfecta because of paternal mosaicism: Gly862?Ser substitution in a type I collagen gene (COL1A1)

Abstract

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 alpha 1 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 (Gly832, Gly844 and Gly901) which is associated with nonlethal phenotypes and which is located between two lethal clusters. In the cases studied here, a Gly862-->Ser mutation was identified that is located inside the nonlethal cluster.

Osteogenesis imperfecta: Mosaicism and refinement of the genotype-phenotype map in OI type III

“…Our observations underline the importance of considering mosaicism also in non-lethal OI. In such families mosaicism may explain the recurrence and the intrafamilial variability of the OI phenotype (Namikawa et al, 1995;Raghunath et al, 1995;Lund et al, 1997).…”

The Influence of Premeiotic Clusters of Mutation on Indirect Estimations of Mutation Rate

“…Some studies, for example, have identifi ed over 40% of mutant gametes in human individuals [25,26] . Hence, if r is assumed to be 0.4 and N = 3,000, then c is about 1.4 and c / 1 becomes 1.040, a 4.0% increase in mutation rates.…”

The Fundamental Theorem of Neutral Evolution: Rates of Substitution and Mutation Should Factor in Premeiotic Clusters

“…In a review of 20 genetic syndromes in humans over 10% of families with new mutations had them arise in clusters (Selby, Woodruff, and Thompson, unpublished data) and over 40% of sperm and oocytes from humans can have a new mutation (Sachs et al, 1990;Edwards et al, 1992;Sommer, Scaringe & Hill, 2001;Yoon et al, 2003). In addition, recurrence risks of 7-33% have been reported for subsequent siblings due to germinal mosaics (Hartl, 1971;Wijsman, 1991;Young, 1991;van Essen et al, 1992;Cooper & Krawczak, 1993;Mottes et al, 1993;Bridges, 1994;Namikawa et al, 1995). Clearly, premeiotic clusters of mutation, including nucleotide substitutions, are common in humans, and one assumes in other animals with limited family sizes.…”