DGI-associated c.2525delG Founder Mutation Identified in American and British Caucasians

Objective: A c.2525delG mutation in the DPP domain of DSPP was previously shown to cause dentinogenesis imperfecta (DGI) in four apparently unrelated Caucasian families. All four were found through haplotype analysis to be identical by descent (McKnight et al., Human Mutation 2008). We hypothesized that this mutation could be widely spread among Caucasian patients with DGI within the US and may have originated in Europe. Methods: British and North American Caucasian patients clinically diagnosed with DGI were analyzed by sequencing the DSPP gene and haplotyping the surrounding 3.5Mb of genomic DNA. A dot blot method was also established to obtain results without sequencing. Results: Three British and two additional American families were found to have the c.2525delG mutation that were identical by descent to each other and to the original four Caucasian families previously described. A single British family had a crossover event between markers D4S2409 and D4S1534 which are located 1.7 Mb and 2.2 MB upstream of the DSPP gene, respectively. In our laboratory, this c.2525delG mutation has been identified in over 80% of the DGI samples prescreened to rule out mutations in DSP suggesting this may represent the most frequent mutation among Caucasians with DGI. We have designed a simple dot blot screening method that bypasses the labor-intensive cloning and sequencing normally required to identify this frameshift mutation in the DSPP repeat domain. Conclusions: The c.2525delG mutation was found to be identical by descent within both British and American DGI families suggesting that the founder mutation occurred in Northern Europe and migrated to America during an early immigration event. A simple dot-blot analysis was developed that can provide a rapid, non sequence-based analysis of this relatively common mutation within Caucasian DGI families. (Supported by DIR/NIDCR/NIH/DHHS)