A missense variant in specificity protein 6 (SP6) is associated with amelogenesis imperfecta
| Autor: | Fatima Nadat, Chris F. Inglehearn, Laura Wilkinson Hewitt, Alan J. Mighell, Claire E. L. Smith, Helen D. Rodd, James A. Poulter, Laura L. E. Whitehouse, Thomas A. Edwards, Brian R. Jackson, Iain W. Manfield |
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| Rok vydání: | 2020 |
| Předmět: |
AcademicSubjects/SCI01140
Male 0301 basic medicine Candidate gene Amelogenesis Imperfecta viruses Kruppel-Like Transcription Factors Mutation Missense Autophagy-Related Proteins Biology 03 medical and health sciences 0302 clinical medicine Dental Enamel Proteins stomatognathic system Mutant protein Exome Sequencing Ameloblasts Genetics medicine Humans Missense mutation Genetic Predisposition to Disease AMBN Amelogenesis imperfecta Dental Enamel Promoter Regions Genetic Molecular Biology Genetics (clinical) Adaptor Proteins Signal Transducing Cell Proliferation Inner enamel epithelium fungi Cell Differentiation General Medicine Amelogenesis medicine.disease Pedigree DNA-Binding Proteins 030104 developmental biology Haplotypes Female General Article Ameloblast Tooth 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddaa041 |
| Popis: | Amelogenesis is the process of enamel formation. For amelogenesis to proceed, the cells of the inner enamel epithelium (IEE) must first proliferate and then differentiate into the enamel-producing ameloblasts. Amelogenesis imperfecta (AI) is a heterogeneous group of genetic conditions that result in defective or absent tooth enamel. We identified a 2 bp variant c.817_818GC>AA in SP6, the gene encoding the SP6 transcription factor, in a Caucasian family with autosomal dominant hypoplastic AI. The resulting missense protein change, p.(Ala273Lys), is predicted to alter a DNA-binding residue in the first of three zinc fingers. SP6 has been shown to be crucial to both proliferation of the IEE and to its differentiation into ameloblasts. SP6 has also been implicated as an AI candidate gene through its study in rodent models. We investigated the effect of the missense variant in SP6 (p.(Ala273Lys)) using surface plasmon resonance protein-DNA binding studies. We identified a potential SP6 binding motif in the AMBN proximal promoter sequence and showed that wild-type (WT) SP6 binds more strongly to it than the mutant protein. We hypothesize that SP6 variants may be a very rare cause of AI due to the critical roles of SP6 in development and that the relatively mild effect of the missense variant identified in this study is sufficient to affect amelogenesis causing AI, but not so severe as to be incompatible with life. We suggest that current AI cohorts, both with autosomal recessive and dominant disease, be screened for SP6 variants. |
| Databáze: | OpenAIRE |
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