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A novel splice acceptor mutation in the DSPP gene causing dentinogenesis imperfecta type II

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Abstract

The dentin sialophosphoprotein (DSPP) gene (4q21.3) encodes two major noncollagenous dentin matrix proteins: dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). Defects in the human gene encoding DSPP cause inherited dentin defects, and these defects can be associated with bilateral progressive high-frequency sensorineural hearing loss. Clinically, five different patterns of inherited dentin defects are distinguished and are classified as dentinogenesis imperfecta (DGI) types I, II, and III, and dentin dysplasia types I and II. The genetic basis for this clinical heterogeneity is unknown. Among the 11 members recruited from the studied kindred, five were affected with autosomal dominant DGI type II. The mutation (g.1188C→G, IVS2-3C→G) lay in the third from the last nucleotide of intron 2 and changed its sequence from CAG to GAG. The mutation was correlated with the affection status and was absent in 104 unaffected individuals (208 alleles) with the same ethnic and geological background. The proband was in the primary dentition stage and presented with multiple pulp exposures. The occlusal surface of his dental enamel was generally abraded, and the dentin was heavily worn and uniformly shaded brown. The dental pulp chambers appeared originally to be within normal limits without any sign of obliteration, but over time (by age 4), the pulp chambers became partially or completely obliterated. The oldest affected member (age 59) showed mild hearing loss at high-frequency (8 kHz). Permanent dentition was severely affected in the adults, who had advanced dental attrition, premature loss of teeth, and extensive dental reconstruction.

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References

  • Bayes M, Hartung AJ, Ezer S, Pispa J, Thesleff I, Srivastava AK, Kere J (1998) The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats. Hum Mol Genet 7:1661–1669

    Article  CAS  PubMed  Google Scholar 

  • Bischoff AM, Luijendijk MW, Huygen PL, Duijnhoven G van, De Leenheer EM, Oudesluijs GG, Van Laer L, Cremers FP, Cremers CW, Kremer H (2004) A novel mutation identified in the DFNA5 gene in a Dutch family: a clinical and genetic evaluation. Audiol Neurotol 9:34–46

    Article  CAS  Google Scholar 

  • Bixler D (1976) Heritable disorders affecting dentin. In: Stewart RE, Prescott GH (eds) Oral facial genetics. Mosby, St. Louis, pp 227–261

  • Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336

    Article  CAS  PubMed  Google Scholar 

  • Butler WT (1987) Dentin-specific proteins. Methods Enzymol 145:290–303

    Article  CAS  PubMed  Google Scholar 

  • Butler WT (1992) Dentin extracellular matrix and dentinogenesis. Oper Dent 5:18–23

    Google Scholar 

  • Butler WT, Brunn JC, Qin C (2003) Dentin extracellular matrix (ECM) proteins: comparison to bone ECM and contribution to dynamics of dentinogenesis. Connect Tissue Res 44:171–178

    CAS  PubMed  Google Scholar 

  • Clark F, Thanaraj TA (2002) Categorization and characterization of transcript-confirmed constitutively and alternatively spliced introns and exons from human. Hum Mol Genet 11:451–464

    Article  CAS  PubMed  Google Scholar 

  • Dean JA, Hartsfield JK Jr, Wright JT, Hart TC (1997) Dentin dysplasia, type II linkage to chromosome 4q. J Craniofac Genet Dev Biol 17:172–177

    CAS  PubMed  Google Scholar 

  • Dimuzio MT, Veis A (1978) Phosphophoryns—major noncollagenous proteins of rat incisor dentin. Calcif Tissue Res 25:169–178

    CAS  PubMed  Google Scholar 

  • Gajko-Galicka A (2002) Mutations in type I collagen genes resulting in osteogenesis imperfecta in humans. Acta Biochim Pol 49:433–441

    PubMed  Google Scholar 

  • Kere J, Srivastava AK, Montonen O, Zonana J, Thomas N, Ferguson B, Munoz F, Morgan D, Clarke A, Baybayan P, Chen EY, Ezer S, Saarialho-Kere U del, Chapelle A, Schlessinger D (1996) X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 13:409–416

    CAS  PubMed  Google Scholar 

  • Krawczak M, Reiss J, Cooper DN (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 90:41–54

    CAS  PubMed  Google Scholar 

  • Lammi L, Halonen K, Pirinen S, Thesleff I, Arte S, Nieminen P (2003) A missense mutation in PAX9 in a family with distinct phenotype of oligodontia. Eur J Hum Genet 11:866–871

    Article  CAS  PubMed  Google Scholar 

  • Lawrence HP, Garcia RI, Essick GK, Hawkins R, Krall EA, Spiro A III, Vokonas PS, Kong L, King T, Koch GG (2001) A longitudinal study of the association between tooth loss and age-related hearing loss. Spec Care Dent 21:129–140

    CAS  Google Scholar 

  • Leaver AG, Triffitt JT, Holbrook IB (1975) Newer knowledge of non-collagenous protein in dentin and cortical bone matrix. Clin Orthop 110:269–292

    CAS  PubMed  Google Scholar 

  • Linde A (1989) The extracellular matrix of dental pulp and dentin. J Dent Res 64:523–529

    Google Scholar 

  • Linde A, Bhown M, Butler WT (1980) Noncollagenous proteins of dentin. A re-examination of proteins from rat incisor dentin utilizing techniques to avoid artifacts. J Biol Chem 255:5931–5942

    CAS  PubMed  Google Scholar 

  • MacDougall M, Simmons D, Luan X, Nydegger J, Feng J, Gu TT (1997) Dentin phosphoprotein and dentin sialoprotein are cleavage products expressed from a single transcript coded by a gene on human chromosome 4. Dentin phosphoprotein DNA sequence determination. J Biol Chem 272:835–842

    Article  CAS  PubMed  Google Scholar 

  • Malmgren B, Lindskog S (2003) Assessment of dysplastic dentin in osteogenesis imperfecta and dentinogenesis imperfecta. Acta Odontol Scand 61:72–80

    Article  CAS  PubMed  Google Scholar 

  • Malmgren B, Lindskog S, Elgadi A, Norgren S (2004) Clinical, histopathologic, and genetic investigation in two large families with dentinogenesis imperfecta type II. Hum Genet 114:491–498

    Article  CAS  PubMed  Google Scholar 

  • Mann S, Webb J, Williams RJP (1989) Biomineralization, chemical and biochemical perspectives. Weinheim, New York

  • Maquat LE (2002) Molecular biology. Skiing toward nonstop mRNA decay. Science 295:2221–2222

    Article  CAS  PubMed  Google Scholar 

  • Miletich I, Sharpe PT (2003) Normal and abnormal dental development. Hum Mol Genet 12:R69–R73

    Article  CAS  PubMed  Google Scholar 

  • Moore MJ (2002) RNA events. No end to nonsense. Science 298:370–371

    Article  CAS  PubMed  Google Scholar 

  • Nagasaka H, Matsukubo T, Takaesu Y, Kobayashi Y, Sato T, Ishikawa T (2002) Changes and equalization in hearing level induced by dental treatment and instruction in bilaterally equalized chewing: a clinical report. Bull Tokyo Dent Coll 43:243–250

    PubMed  Google Scholar 

  • Oliveira RJ, Hammer B, Stillman A, Holm J, Jons C, Margolis RH (1992) A look at ear canal changes with jaw motion. Ear Hear 13:464–466

    CAS  PubMed  Google Scholar 

  • Padgett RA, Grabowski PJ, Konarska MM, Seiler S, Sharp PA (1986) Splicing of messenger RNA precursors. Annu Rev Biochem 55:1119–1150

    Article  CAS  PubMed  Google Scholar 

  • Pallos D, Hart PS, Cortelli JR, Vian S, Wright JT, Korkko J, Brunoni D, Hart TC (2001) Novel COL1A1 mutation (G599C) associated with mild osteogenesis imperfecta and dentinogenesis imperfecta. Arch Oral Biol 46:459–470

    Article  CAS  PubMed  Google Scholar 

  • Qin C, Brunn JC, Jones J, George A, Ramachandran A, Gorski JP, Butler WT (2001) A comparative study of sialic acid-rich proteins in rat bone and dentin. Eur J Oral Sci 109:133–141

    Article  CAS  PubMed  Google Scholar 

  • Qin C, Brunn JC, Cadena E, Ridall A, Tsujigiwa H, Nagatsuka H, Nagai N, Butler WT (2002) The expression of dentin sialophosphoprotein gene in bone. J Dent Res 81:392–394

    CAS  PubMed  Google Scholar 

  • Qin C, Brunn JC, Cadena E, Ridall A, Butler WT (2003) Dentin sialoprotein in bone and dentin sialophosphoprotein gene expressed by osteoblasts. Connect Tissue Res 44:179–183

    CAS  PubMed  Google Scholar 

  • Rajpar MH, Koch MJ, Davies RM, Mellody KT, Kielty CM, Dixon MJ (2002) Mutation of the signal peptide region of the bicistronic gene DSPP affects translocation to the endoplasmic reticulum and results in defective dentine biomineralization. Hum Mol Genet 11:2559–2565

    Article  CAS  PubMed  Google Scholar 

  • Ritchie HH, Shigeyama Y, Somerman MJ, Butler WT (1996) Partial cDNA sequencing of mouse dentine sialoprotein and detection of its specific expression by odontoblasts. Arch Oral Biol 41:571–575

    Article  CAS  PubMed  Google Scholar 

  • Semina EV, Reiter R, Leysens NJ, Alward WL, Small KW, Datson NA, Siegel-Bartelt J, Bierke-Nelson D, Bitoun P, Zabel BU, Carey JC, Murray JC (1996) Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392–399

    CAS  PubMed  Google Scholar 

  • Shields ED, Bixler D, el-Kafrawy AM (1973) A proposed classification for heritable human dentine defects with a description of a new entity. Arch Oral Biol 18:543–553

    Article  CAS  PubMed  Google Scholar 

  • Sreenath T, Thyagarajan T, Hall B, Longenecker G, D’Souza R, Hong S, Wright JT, MacDougall M, Sauk J, Kulkarni AB (2003) Dentin sialophosphoprotein knockout mouse teeth display widened predentin zone and develop defective dentin mineralization similar to human dentinogenesis imperfecta type III. J Biol Chem 278:24874–24880

    Article  CAS  PubMed  Google Scholar 

  • Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, Abeysinghe S, Krawczak M, Cooper DN (2003) Human gene mutation database (HGMD): 2003 update. Hum Mutat 21:577–581

    Article  CAS  PubMed  Google Scholar 

  • Stockton DW, Das P, Goldenberg M, D’Souza RN, Patel PI (2000) Mutation of PAX9 is associated with oligodontia. Nat Genet 24:18–19

    Article  CAS  PubMed  Google Scholar 

  • Thesleff I (2003) Epithelial-mesenchymal signalling regulating tooth morphogenesis. J Cell Sci 116:1647–1648

    Article  CAS  PubMed  Google Scholar 

  • Thesleff I, Jernvall J (1997) The enamel knot: a putative signaling center regulating tooth development. Cold Spring Harb Symp Quant Biol 62:257–267

    CAS  PubMed  Google Scholar 

  • Thesleff I, Sharpe P (1997) Signalling networks regulating dental development. Mech Dev 67:111–123

    Article  CAS  PubMed  Google Scholar 

  • Tucker AS, Sharpe PT (1999) Molecular genetics of tooth morphogenesis and patterning: the right shape in the right place. J Dent Res 78:826–834

    CAS  PubMed  Google Scholar 

  • Vastardis H (2000) The genetics of human tooth agenesis: new discoveries for understanding dental anomalies. Am J Orthod Dentofacial Orthop 117:650–656

    Article  CAS  PubMed  Google Scholar 

  • Vastardis H, Karimbux N, Suthua SW, Seidman JG, Seidman CE (1996) A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat Genet 13:417–421

    CAS  PubMed  Google Scholar 

  • Veis A, Perry A (1967) The phosphoprotein of the dentin matrix. Biochemistry 6:2409–2416

    CAS  PubMed  Google Scholar 

  • Wagner E, Lykke-Andersen J (2002) mRNA surveillance: the perfect persist. J Cell Sci 115:3033–3038

    CAS  PubMed  Google Scholar 

  • Xiao S, Yu C, Chou X, Yuan W, Wang Y, Bu L, Fu G, Qian M, Yang J, Shi Y, Hu L, Han B, Wang Z, Huang W, Liu J, Chen Z, Zhao G, Kong X (2001) Dentinogenesis imperfecta 1 with or without progressive hearing loss is associated with distinct mutations in DSPP. Nat Genet 27:201–204

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Zhao J, Li C, Gao S, Qiu C, Liu P, Wu G, Qiang B, Lo WH, Shen Y (2001) DSPP mutation in dentinogenesis imperfecta Shields type II. Nat Genet 27:151–152

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all the family members for their cooperation, and the students of Seoul National University, School of Dentistry for donating their blood for this study. This investigation was supported in part by the Foundation of the American Academy of Pediatric Dentistry, and USPHS Research Grants DE12769 and DE11301 from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA.

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Authors and Affiliations

  1. Department of Biological and Material Sciences, University of Michigan Dental Research Laboratory, 1210 Eisenhower Place, Ann Arbor, MI 48108, USA

    J.-W. Kim, J. C.-C. Hu & J. P. Simmer

  2. Department of Pediatric Dentistry and Dental Research Institute, College of Dentistry, Seoul National University, 28-2 Yongon-Dong, Chongno-Gu, Seoul, 110-768, Korea

    J.-W. Kim, K.-T. Jang, S.-H. Lee, C.-C. Kim & S.-H. Hahn

  3. Department of Pediatric Dentistry, College of Dentistry, Kyungpook National University, 2-188-1 Samduk-Dong, Jung-Gu, Daegu, 700-412, Korea

    S.-H. Nam

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  1. J.-W. Kim
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Correspondence to J. P. Simmer.

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Kim, JW., Nam, SH., Jang, KT. et al. A novel splice acceptor mutation in the DSPP gene causing dentinogenesis imperfecta type II. Hum Genet 115, 248–254 (2004). https://doi.org/10.1007/s00439-004-1143-5

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