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Mutations in RELT cause autosomal recessive amelogenesis imperfecta
- Source :
- Clinical Genetics
- Publication Year :
- 2019
- Publisher :
- WILEY, 2019.
-
Abstract
- WOS: 000458956100004 PubMed ID: 30506946 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. National Institute of Dental and Craniofacial Research [DE015846DE016276]; National Research Foundation of Korea [NRF-2017R1A2A2A05069281NRF-2018R1A5A2024418] National Institute of Dental and Craniofacial Research, Grant/Award Number: DE015846DE016276; National Research Foundation of Korea, Grant/Award Number: NRF-2017R1A2A2A05069281NRF-2018R1A5A2024418
- Subjects :
- 0301 basic medicine
Proband
Pathology
medicine.medical_specialty
Genotype
Amelogenesis Imperfecta
Relt Knockout
RNA Splicing
Genes, Recessive
Biology
Receptors, Tumor Necrosis Factor
Consanguinity
03 medical and health sciences
Incisor
stomatognathic system
Exome Sequencing
Genetics
medicine
RELT
Humans
Genetic Predisposition to Disease
Amelogenesis imperfecta
Genetic Association Studies
Germ-Line Mutation
In Situ Hybridization
Genetics (clinical)
Hypomineralized
Enamel paint
Original Articles
Amelogenesis
medicine.disease
Pedigree
stomatognathic diseases
Phenotype
030104 developmental biology
medicine.anatomical_structure
Odontoblast
Enamel
visual_art
Mutation
visual_art.visual_art_medium
Original Article
Ameloblast
Tooth
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Clinical Genetics
- Accession number :
- edsair.doi.dedup.....da099998159c9b6eb2c4f0d35d1e180f