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Hum Mutat. 2008 Dec;29(12):1392-404. doi: 10.1002/humu.20783.

A comprehensive analysis of normal variation and disease-causing mutations in the human DSPP gene.

Author information

1
Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, Maryland 20892, USA.

Abstract

Within nine dentin dysplasia (DD) (type II) and dentinogenesis imperfecta (type II and III) patient/families, seven have 1 of 4 net -1 deletions within the approximately 2-kb coding repeat domain of the DSPP gene while the remaining two patients have splice-site mutations. All frameshift mutations are predicted to change the highly soluble DSPP protein into proteins with long hydrophobic amino acid repeats that could interfere with processing of normal DSPP and/or other secreted matrix proteins. We propose that all previously reported missense, nonsense, and splice-site DSPP mutations (all associated with exons 2 and 3) result in dominant phenotypes due to disruption of signal peptide-processing and/or related biochemical events that also result in interference with protein processing. This would bring the currently known dominant forms of the human disease phenotype in agreement with the normal phenotype of the heterozygous null Dspp (-/+) mice. A study of 188 normal human chromosomes revealed a hypervariable DSPP repeat domain with extraordinary rates of change including 20 slip-replication indel events and 37 predominantly C-to-T transition SNPs. The most frequent transition in the primordial 9-basepair (bp) DNA repeat was a sense-strand CpG site while a CpNpG (CAG) transition was the second most frequent SNP. Bisulfite-sequencing of genomic DNA showed that the DSPP repeat can be methylated at both motifs. This suggests that, like plants and some animals, humans methylate some CpNpG sequences. Analysis of 37 haplotypes of the highly variable DSPP gene from geographically diverse people suggests it may be a useful autosomal marker in human migration studies.

PMID:
18521831
PMCID:
PMC5534847
DOI:
10.1002/humu.20783
[Indexed for MEDLINE]
Free PMC Article

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