Refinement of the Dentinogenesis Imperfecta Type II Locus to an Interval of Less Than 2 CentiMorgans at Chromosome 4q21 and the Creation of a Yeast Artificial Chromosome Contig of the Critical Region

Abstract

Dentinogenesis imperfecta type II is an autosomal-dominant disorder of dentin formation which has been mapped to the 6.6 centiMorgan D4S2691-D4S2692 interval at human chromosome 4q21. In the current investigation, the use of four short tandem repeat polymorphisms has allowed the critical region to be refined to an interval of less than 2 centiMorgans defined by recombination events in unrelated, affected individuals from two families both of which show independent evidence for linkage to chromosome 4q21. The creation of a yeast artificial chromosome contig of this newly defined interval has allowed us to demonstrate that the critical region encompasses approximately 2 Mb of DNA and that the dentin-specific gene, dentin sialoprotein, maps to this interval within 300 kb of dentin matrix acidic phosphoprotein 1 and bone sialoprotein. Moreover, dentin sialoprotein shows no recombination with the dentinogenesis imperfecta type II phenotype. Dentin sialoprotein is therefore a candidate for the dentinogenesis imperfecta type II locus.

Dentin Sialoprotein (DSP) Has Limited Effects on In Vitro Apatite Formation and Growth

“…It should be noted, however, that some of the Ca and/or phosphate that diffuses into the gels may interact with the protein and contribute to the protein's nucleation, and/or inhibitory potential. DSP is synthesized by tooth-forming cells and preameloblasts [1,2,7,18], and is localized at the protein (immunohistochemical) and gene (in situ hybridization) levels in newly forming dentin [23]. Its accumulation at the mineralization front implies a role in mineralization, but, on a weight per weight or mole per mole basis, DSP was not as effective an inhibitor of apatite formation as osteopontin [13], having ∼50% the efficacy of OPN at the same molar concentration.…”

“…Although its sequence shows several potential phosphorylation sites [22], DSP contains about one residue of phosphate per molecule [Butler WT, unpublished]. Although DSP is unrelated in amino acid sequence to OPN and BSP [22], genes for the three sialoproteins are located close to each other on human chromosome 4 [23]. In developing dentin, DSP is expressed in odontoblasts and in preameloblasts [8,24,25].…”

DMP1 and DSPP: Evidence for Duplication and Convergent Evolution of Two SIBLING Proteins

“…By the late 1990s the genes encoding 4 of them, i.e. integrin-binding sialoprotein (IBSP) that encodes BSP, SPP1 (or OPN), dentin matrix protein-1 (DMP1), and dentin sialophosphoprotein (DSPP), were mapped to a shared region of human chromosome 4 (mouse chromosome 5) suggesting that their frequent coexpression may be controlled, in part, by relaxation of the local chromosomal regions [Crosby et al, 1996;Feng et al, 1998;Aplin et al, 1999]. Around the millennium, the first drafts of the human and mouse genome sequences enabled us for the first time to report that 4 of the bone/tooth phosphoprotein genes (IBSP, SPP1, DMP1, and DSPP) were tandem genes interrupted only by 1 additional gene, i.e.…”

Dentin phosphoprotein compound mutation in dentin sialophosphoprotein causes dentinogenesis imperfecta type III

“…Linkage analyses demonstrated that the DGI-III locus is located on human chromosome 4q21.1-21.3 within a 6.6 cM region [Boughman et al, 1986;MacDougall et al, 1999]. This region overlaps the critical loci for DGI-type II (2 cM between GATA62A11 and D4S1563) [Aplin et al, 1999] and dentin dysplasia type II (DD-II) (14.1 cM between D4S3291 and SSP1) [Dean et al, 1997] suggesting that these three dentin diseases maybe allelic or due to separate genes that are tightly linked.A gene cluster of dentin/bone extracellular matrix proteins has been characterized on human chromosome 4q21 [MacDougall et al, 1999. Genes mapping to this region include osteopontin (OPN, also known as secreted phosphoprotein 1 SPP1), bone sialophosphoprotein (IBSP), matrix extracellular phosphoglycoprotein (MEPE, also known as osteoblast/osteocyte factor 45-OF45), dentin matrix protein 1 (DMP1), and dentin sialophosphoprotein (DSPP) [MacDougall, 2003].…”