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A comprehensive analysis of normal variation and disease‐causing mutations in the human DSPP gene
Author(s) -
McKnight Dianalee A.,
Suzanne Hart P.,
Hart Thomas C.,
Hartsfield James K.,
Wilson Anne,
Wright J. Timothy,
Fisher Larry W.
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20783
Subject(s) - biology , genetics , frameshift mutation , exon , gene , indel mutation , missense mutation , dentinogenesis imperfecta , mutation , single nucleotide polymorphism , genotype , anatomy , osteogenesis imperfecta
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 ∼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. Hum Mutat 0, 1–13, 2008. Published 2008, Wiley‐Liss, Inc.