2. Academic Validation
  3. Mutations in RELT cause autosomal recessive amelogenesis imperfecta

Mutations in RELT cause autosomal recessive amelogenesis imperfecta

  • Clin Genet. 2019 Mar;95(3):375-383. doi: 10.1111/cge.13487.
Jung-Wook Kim 1 2,  Hong Zhang 3,  Figen Seymen 4,  Mine Koruyucu 4,  Yuanyuan Hu 3,  Jenny Kang 1,  Youn J Kim 2,  Atsushi Ikeda 5,  Yelda Kasimoglu 4,  Merve Bayram 6,  Chuhua Zhang 3,  Kazuhiko Kawasaki 7,  John D Bartlett 5,  Thomas L Saunders 8,  James P Simmer 3,  Jan C-C Hu 3
Affiliations

Affiliations

  • 1 Department of Pediatric Dentistry & Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
  • 2 Department of Molecular Genetics & the Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
  • 3 Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan.
  • 4 Department of Pedodontics, Faculty of Dentistry, Istanbul University, Istanbul, Turkey.
  • 5 Division of Biosciences, The Ohio State University, College of Dentistry, Columbus, Ohio.
  • 6 Department of Pedodontics, Faculty of Dentistry, Istanbul Medipol University, Istanbul, Turkey.
  • 7 Department of Anthropology, Penn State University, University Park, Pennsylvania.
  • 8 Department of Internal Medicine, Division of Molecular, Medicine and Genetics, University of Michigan Medical School, Ann Arbor, Michigan.
PMID: 30506946 DOI: 10.1111/cge.13487
Abstract

Amelogenesis imperfecta (AI) is a collection of isolated (non-syndromic) inherited diseases affecting dental enamel formation or a clinical phenotype in syndromic conditions. We characterized three consanguineous AI families with generalized irregular hypoplastic enamel with rapid attrition that perfectly segregated with homozygous defects in a novel gene: RELT that is a member of the tumor necrosis factor receptor superfamily (TNFRSF). RNAscope in situ hybridization of wild-type mouse molars and incisors showed specific Relt mRNA expression by secretory stage ameloblasts and by odontoblasts. Relt-/- mice generated by CRISPR/Cas9 exhibited incisor and molar enamel malformations. Relt-/- enamel had a rough surface and underwent rapid attrition. Normally unmineralized spaces in the deep enamel near the dentino-enamel junction (DEJ) were as highly mineralized as the adjacent enamel, which likely altered the mechanical properties of the DEJ. Phylogenetic analyses showed the existence of selective pressure on RELT gene outside of tooth development, indicating that the human condition may be syndromic, which possibly explains the history of small stature and severe childhood infections in two of the probands. Knowing a TNFRSF member is critical during the secretory stage of enamel formation advances our understanding of amelogenesis and improves our ability to diagnose human conditions featuring enamel malformations.

Keywords

Relt knockout; amelogenesis imperfecta; enamel; hypomineralized; tooth.

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