Document Detail

A comprehensive analysis of normal variation and disease-causing mutations in the human DSPP gene.
MedLine Citation:
PMID:  18521831     Owner:  NLM     Status:  MEDLINE    
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.
Dianalee A McKnight; P Suzanne Hart; Thomas C Hart; James K Hartsfield; Anne Wilson; J Timothy Wright; Larry W Fisher
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural    
Journal Detail:
Title:  Human mutation     Volume:  29     ISSN:  1098-1004     ISO Abbreviation:  Hum. Mutat.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-27     Completed Date:  2009-01-08     Revised Date:  2010-02-05    
Medline Journal Info:
Nlm Unique ID:  9215429     Medline TA:  Hum Mutat     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1392-404     Citation Subset:  IM    
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.
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MeSH Terms
Amino Acid Sequence
Base Sequence
DNA Mutational Analysis
Dentin Dysplasia / genetics*
Dentinogenesis Imperfecta / genetics*
Extracellular Matrix Proteins / genetics*
Molecular Sequence Data
Reg. No./Substance:
0/Extracellular Matrix Proteins; 0/dentin sialophosphoprotein

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