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Dentin sialophosphoprotein (DSPP) is a secreted phosphoprotein critical for dentin mineralization. Heterozygous DSPP mutations cause autosomal-dominant dentinogenesis imperfecta (DI), characterized by opalescent, discolored teeth prone to rapid wear and pulp exposures. Radiographically, affected teeth often exhibit enlarged pulp chambers and cervical constrictions. Early molecular diagnosis enables timely dental management to prevent functional impairment and aesthetic sequelae.
Pathogenic DSPP variants have been reported in at least 27 affected individuals across three unrelated families, with complete cosegregation in each pedigree (4 patients) [PMID:19131317]; (4 patients) [PMID:23018043]; (19 patients) [PMID:38630328]. The inheritance is consistently autosomal dominant, spanning four generations in kindreds with full penetrance. Segregation of distinct missense, nonsense, splice-site, and frameshift variants in exon 2 and the repeat domain confirms the role of DSPP in DI.
Over 59 different DSPP mutations have been documented, including 45 missense, 6 splice-site, and 8 frameshift variants clustering in the signal peptide and Ca2+-binding repeat regions [PMID:39806231]. Recurrent variants such as c.50C>T (p.Pro17Leu) and c.53T>A (p.Val18Asp) disrupt the IPV motif, while frameshifts in the repeat domain produce hydrophobic C-terminal extensions. One exemplar pathogenic variant is c.53T>A (p.Val18Asp).
In vitro splicing assays validated that splice-junction mutations variably induce exon 3 skipping, altering DSPP transcript levels [PMID:21736673]. Cellular studies show that IPV-motif mutants (e.g., p.Ala15Val, p.Val18Asp) are retained in the rough endoplasmic reticulum, exerting dominant-negative effects on wild-type DSPP trafficking [PMID:22392858]. BMP1 isoforms cleave DSPP at the MQGDD motif, a necessary activation step for dentinogenesis; non-cleavable D452A-DSPP transgenic mice failed to rescue Dspp-null defects, confirming the essential role of proteolytic processing [PMID:20079836][PMID:22798071].
Dspp knockout mice are phenotypically normal when heterozygous but develop severe dentin defects when homozygous, mirroring human DI. Transgenic expression of mutant DSPP alleles in mouse models induces ER stress and dentin malformations, supporting a dominant-negative mechanism due to impaired secretion and disrupted matrix assembly.
DSPP genetic testing is recommended for individuals with clinical and radiographic features of DI to guide early intervention, family counseling, and management strategies. Identification of specific DSPP variants informs prognosis and potential enrolment in emerging therapeutic trials.
Key Take-home: DSPP is definitively associated with autosomal-dominant dentinogenesis imperfecta; molecular diagnosis enables personalized dental management and genetic counseling.
Gene–Disease AssociationDefinitivePathogenic DSPP variants segregate with autosomal-dominant dentinogenesis imperfecta in multiple unrelated families across four generations, with concordant functional and animal model data. Genetic EvidenceStrongHeterozygous DSPP mutations identified in >27 affected individuals across >3 families with complete co-segregation and diverse variant classes (missense, splice, frameshift)[PMID:19131317][PMID:23018043][PMID:38630328]. Functional EvidenceModerateIn vitro splicing, ER-trafficking assays, proteolytic processing studies and transgenic mouse models consistently demonstrate dominant-negative mechanisms and essential DSPP processing for dentinogenesis [PMID:21736673][PMID:22392858][PMID:20079836][PMID:22798071]. |