title: A DSPP mutation causing dentinogenesis imperfecta and characterization of the mutational effect.
abstract: Mutations in the DSPP gene have been identified in nonsyndromic hereditary dentin defects, but the genotype-phenotype correlations are not fully understood. Recently, it has been demonstrated that the mutations of DSPP affecting the IPV leader sequence result in mutant DSPP retention in rough endoplasmic reticulum (ER). In this study, we identified a Korean family with dentinogenesis imperfecta type III. To identify the disease causing mutation in this family, we performed mutational analysis based on candidate gene sequencing. Exons and exon-intron boundaries of DSPP gene were sequenced, and the effects of the identified mutation on the pre-mRNA splicing and protein secretion were investigated. Candidate gene sequencing revealed a mutation (c.50C > T, p.P17L) in exon 2 of the DSPP gene. The splicing assay showed that the mutation did not influence pre-mRNA splicing. However, the mutation interfered with protein secretion and resulted in the mutant protein remaining largely in the ER. These results suggest that the mutation affects ER-to-Golgi apparatus export and results in the reduction of secreted DSPP and ER overload. This may induce cell stress and damage processing and/or transport of dentin matrix proteins or other critical proteins.
authors.affiliation: Department of Pediatric Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, 275-1 Yongon-dong, Chongno-gu, Seoul 110-768, Republic of Korea.
authors.forename: Sook-Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Kyung-Eun
authors.initials: KE
authors.lastname: Lee
authors.forename: Su Jeong
authors.initials: SJ
authors.lastname: Song
authors.forename: Hong-Keun
authors.initials: HK
authors.lastname: Hyun
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Jung-Wook
authors.initials: JW
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D003804:Dentin / Q000502:physiology; D003811:Dentinogenesis Imperfecta / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D056910:Republic of Korea; D012795:Sialoglycoproteins / Q000235:genetics*; D000099311:Dentin Sialophosphoprotein
chemical_list: D016326:Extracellular Matrix Proteins; D010750:Phosphoproteins; D012795:Sialoglycoproteins; D000099311:Dentin Sialophosphoprotein