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Complex Genetics of Dentin Disorders

December 18, 2008

Diagram showing part of the normal gene sequenceInherited dentin disorders fall into two broad categories:  Dentinogenesis imperfecta (DGI) and dentin dysplasia (DD).  People born with DGI typically have amber-brown, opalescent baby and adult teeth that readily fracture and shed their enamel.  This exposes the dentin and leads to its erosion, often all the way down to their gums. Meanwhile, those with DD have primary teeth that look similar to those with DGI, but they often have almost normal adult teeth with only mild discoloration and some unusual root structures that appear on standard dental X-ray films. Interestingly, despite their clinically distinct phenotypes, or manifestations, both conditions have been linked to alterations of the DSPP gene. 
Over the last few years, efforts to characterize disease-causing mutations in DSPP have expanded into its structurally unique exon five, a bewilderingly repetitive but protein-encoding stretch of the gene. [See the Inside Scoop: Dentin Disorders: The Twists and Turns of Cloning the DSPP gene ].  Recently, two published papers reported that three distinct frameshift mutations early in exon five caused DD, while six other frameshift mutations near the end of the exon were associated with DGI.  Frameshift mutations are changes of one or two bases, or units, of DNA that throw off the normal sequence and amino acid-encoding frame that is read to make the needed protein. These data at first suggested that the geographic locations of a frameshift mutation might determine which dentin disorder a person inherits, DD or DGI.
In the December issue of the Journal of Dental Research, NIDCR scientists and colleagues report that the story likely is more biologically complex.  They found a frameshift mutation in a family with four generations of DD that falls in the portion of exon five previously thought to correlate exclusively with DGI.  The authors speculated that an as-yet unidentified modifying DNA element might explain why similar mutations ultimately result in DGI or DD depending on which family's DSPP gene undergoes the mutation.  "One hypothesis is that this modifying element is directly involved in controlling the amount of DSPP expressed from the mutant allele," the scientists wrote.  The scientists also noted that a corollary hypothesis is normal variants in the messenger RNA, the coding intermediate between gene and protein, may survive longer in the cell resulting in the production of more mutant protein, leading to its disruptive and disease-causing accumulation in the cell.   


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This page last updated: February 26, 2014