Whole exome sequencing identifies an AMBN missense mutation causing severe autosomal-dominant amelogenesis imperfecta and dentin disorders

Abstract

Tooth development is a complex process that involves precise and time-dependent orchestration of multiple genetic, molecular, and cellular interactions. Ameloblastin (AMBN, also named “amelin” or “sheathlin”) is the second most abundant enamel matrix protein known to have a key role in amelogenesis. Amelogenesis imperfecta (AI [MIM: 104500]) refers to a genetically and phenotypically heterogeneous group of conditions characterized by inherited developmental enamel defects. The hereditary dentin disorders comprise a variety of autosomal-dominant genetic symptoms characterized by abnormal dentin structure affecting either the primary or both the primary and secondary teeth. The vital role of Ambn in amelogenesis has been confirmed experimentally using mouse models. Only two cases have been reported of mutations of AMBN associated with non-syndromic human AI. However, no AMBN missense mutations have been reported to be associated with both human AI and dentin disorders. We recruited one kindred with autosomal-dominant amelogenesis imperfecta (ADAI) and dentinogenesis imperfecta/dysplasia characterized by generalized severe enamel and dentin defects. Whole exome sequencing of the proband identified a novel heterozygous C-T point mutation at nucleotide position 1069 of the AMBN gene, causing a Pro to Ser mutation at the conserved amino acid position 357 of the protein. Exfoliated third molar teeth from the affected family members were found to have enamel and dentin of lower mineral density than control teeth, with thinner and easily fractured enamel, short and thick roots, and pulp obliteration. This study demonstrates, for the first time, that an AMBN missense mutation causes non-syndromic human AI and dentin disorders.

Co-Immunoprecipitation Reveals Interactions Between Amelogenin and Ameloblastin via Their Self-Assembly Domains

“…The ability of Ambn C-terminal region to bind calcium has been well-documented ( Yamakoshi et al, 2001 ; Tarasevich et al, 2007 ; Zhang et al, 2011 ) suggesting Ambn’s involvement in mineralization. A recent report of AI with a point mutation in the calcium-binding region of Ambn described enamel with low mineral density ( Lu et al, 2018 ).…”

An Evolutionarily Conserved Helix Mediates Ameloblastin-Cell Interaction

“…Ambn, the second most abundant enamel matrix protein, is a proline-rich, intrinsically disordered macromolecule involved in cell-matrix adhesion, the construction of functional EECM, and enamel mineralization (Fukumoto et al 2004; Zhang, Diekwisch, et al 2011; Wald et al 2017). Mutations such as deletion of AMBN exon 6, a homozygous splice-site mutation (c.532–1G>C), and a C-T point mutation causing a P357S mutation are all associated with human hypoplastic amelogenesis imperfecta (AI) (Poulter et al 2014; Prasad et al 2016; Lu et al 2018). In mouse, deletion of Ambn exons 5 and 6 results in the detachment of ameloblasts, the loss of their polarized organization, and the replacement of enamel by a thin layer of dysplastic mineralized matrix (Fukumoto et al 2004; Wazen et al 2009).…”

AMBN mutations causing hypoplastic amelogenesis imperfecta and Ambn knockout‐NLS‐lacZ knockin mice exhibiting failed amelogenesis and Ambn tissue‐specificity

“…Both of these AMBN defects were associated with a non‐syndromic hypoplastic AI (thin enamel) phenotype. Recently an AMBN single allele mutation (NM_016519.5: c.1069C>T; p.Pro357Ser) was reported to cause a dominant condition with both enamel and dentin defects (Lu et al, ), but the clinical phenotype exactly matched that of dentinogenesis imperfecta, an autosomal dominant condition caused by mutations in DSPP , a gene linked to AMBN on chromosome 4 that contains a large repetitive region that cannot be characterized using whole exome sequence analyses (Yang et al, ).…”