The Modified Shields Classification and 12 Families with Defined DSPP Mutations Public Deposited

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  • Simmer, James P.
    • Other Affiliation: University of Michigan
  • Zhang, Hong
    • Other Affiliation: University of Michigan
  • Moon, Sophie J. H.
    • Other Affiliation: University of Michigan
  • Donnelly, Lori A.-J.
    • Affiliation: School of Dentistry, Department of Oral and Maxillofacial Surgery
  • Lee, Yuan-Ling
    • Other Affiliation: National Taiwan University
  • Seymen, Figen
    • Other Affiliation: Altinbas University
  • Koruyucu, Mine
    • Other Affiliation: Istanbul University
  • Chan, Hui-Chen
    • Other Affiliation: Taipei Municipal WanFang Hospital
  • Lee, Kevin Y.
    • Other Affiliation: Taipei Municipal WanFang Hospital
  • Wu, Suwei
    • Other Affiliation: Taipei Municipal WanFang Hospital
  • Hsiang, Chia-Lan
    • Other Affiliation: Taipei Municipal WanFang Hospital
  • Tsai, Anthony T. P.
    • Other Affiliation: Taipei Municipal WanFang Hospital
  • Slayton, Rebecca L.
    • Other Affiliation: University of Washington
  • Morrow, Melissa
    • Other Affiliation: University of Michigan
  • Wang, Shih-Kai
    • Other Affiliation: National Taiwan University
  • Shields, Edward D.
  • Hu, Jan C.-C.
    • Other Affiliation: University of Michigan
Abstract
  • Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II (DGI-II), and dentinogenesis imperfecta type-III (DGI-III). DSPP mutations fall into two groups: a 5′-group that affects protein targeting and a 3′-group that shifts translation into the −1 reading frame. Using whole-exome sequence (WES) analyses and Single Molecule Real-Time (SMRT) sequencing, we identified disease-causing DSPP mutations in 12 families. Three of the mutations are novel: c.53T>C/p.(Val18Ala); c.3461delG/p.(Ser1154Metfs*160); and c.3700delA/p.(Ser1234Alafs*80). We propose genetic analysis start with WES analysis of proband DNA to identify mutations in COL1A1 and COL1A2 causing dominant forms of osteogenesis imperfecta, 5′-DSPP mutations, and 3′-DSPP frameshifts near the margins of the DSPP repeat region, and SMRT sequencing when the disease-causing mutation is not identified. After reviewing the literature and incorporating new information showing distinct differences in the cell pathology observed between knockin mice with 5′-Dspp or 3′-Dspp mutations, we propose a modified Shields Classification based upon the causative mutation rather than phenotypic severity such that patients identified with 5′-DSPP defects be diagnosed as DGI-III, while those with 3′-DSPP defects be diagnosed as DGI-II.
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  • Article
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  • In Copyright
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  • Attribution 4.0 International
Journal title
  • Genes
Journal volume
  • 13
Journal issue
  • 5
Page start
  • 858
Language
  • English
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  • Publisher
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  • 2073-4425
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