Mutations in the pH-Sensing G-protein-Coupled Receptor GPR68 Cause Amelogenesis Imperfecta.

Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body. This process requires the intricate regulation of ion transport and controlled changes to the pH of the developing enamel matrix. The means by which the enamel organ regulates pH during amelogenesis is largely unknown.

Spectrum of PEX1 and PEX6 variants in Heimler syndrome.

Heimler syndrome (HS) consists of recessively inherited sensorineural hearing loss, amelogenesis imperfecta (AI) and nail abnormalities, with or without visual defects. Recently HS was shown to result from hypomorphic mutations in PEX1 or PEX6, both previously implicated in Zellweger Syndrome Spectrum Disorders (ZSSD). ZSSD are a group of conditions consisting of craniofacial and neurological abnormalities, sensory defects and multi-organ dysfunction.

A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta.

We identified a family in which pitted hypomineralized amelogenesis imperfecta (AI) with premature enamel failure segregated in an autosomal recessive fashion. Whole-exome sequencing revealed a missense mutation (c.586C>A, p.

Whole-exome sequencing, without prior linkage, identifies a mutation in LAMB3 as a cause of dominant hypoplastic amelogenesis imperfecta.

The conventional approach to identifying the defective gene in a family with an inherited disease is to find the disease locus through family studies. However, the rapid development and decreasing cost of next generation sequencing facilitates a more direct approach. Here, we report the identification of a frameshift mutation in LAMB3 as a cause of dominant hypoplastic amelogenesis imperfecta (AI).

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.

Background/aims: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.

Methods: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption).

A silicon cell cycle in a bacterial model of calcium phosphate mineralogenesis.

The prokaryote Corynebacterium matruchotii produces calcium phosphate (bone salt) and may serve as a convenient model for examining individual factors relevant to vertebrate calcification. A factor of current clinical uncertainty is silicon. To investigate its possible role in biomineralisation advanced optical (digital deconvolution and 3D fluorescent image rendering) and electron microscopy (EDX microanalysis and elemental mapping) were applied to calcifying microbial colonies grown in graded Si concentrations (0-60mM).

Cellular uptake and processing of enamel matrix derivative by human periodontal ligament fibroblasts.

Objective: Enamel matrix derivative (EMD), is an extract of porcine developing enamel matrix. Its commercialised form Emdogain, is claimed to stimulate periodontal regeneration by recapitulating original developmental processes, although the mechanism remains unclear. Our objective was to investigate interactions between EMD and human periodontal ligament (HPDL) fibroblasts in vitro.

Mutations in C4orf26, encoding a peptide with in vitro hydroxyapatite crystal nucleation and growth activity, cause amelogenesis imperfecta.

Autozygosity mapping and clonal sequencing of an Omani family identified mutations in the uncharacterized gene, C4orf26, as a cause of recessive hypomineralized amelogenesis imperfecta (AI), a disease in which the formation of tooth enamel fails. Screening of a panel of 57 autosomal-recessive AI-affected families identified eight further families with loss-of-function mutations in C4orf26. C4orf26 encodes a putative extracellular matrix acidic phosphoprotein expressed in the enamel organ.

A mutation in the mouse Amelx tri-tyrosyl domain results in impaired secretion of amelogenin and phenocopies human X-linked amelogenesis imperfecta.

Amelogenesis imperfecta (AI) describes a broad group of clinically and genetically heterogeneous inherited defects of dental enamel bio-mineralization. Despite identification of a number of genetic mutations underlying AI, the precise causal mechanisms have yet to be determined. Using a multi-disciplinary approach, we describe here a mis-sense mutation in the mouse Amelx gene resulting in a Y --> H substitution in the tri-tyrosyl domain of the enamel extracellular matrix protein amelogenin.

Mutations in the beta propeller WDR72 cause autosomal-recessive hypomaturation amelogenesis imperfecta.

Healthy dental enamel is the hardest and most highly mineralized human tissue. Though acellular, nonvital, and without capacity for turnover or repair, it can nevertheless last a lifetime. Amelogenesis imperfecta (AI) is a collective term for failure of normal enamel development, covering diverse clinical phenotypes that typically show Mendelian inheritance patterns.

Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta.

The combination of recessively inherited cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) was first reported by Jalili and Smith in 1988 in a family subsequently linked to a locus on chromosome 2q11, and it has since been reported in a second small family. We have identified five further ethnically diverse families cosegregating CRD and AI. Phenotypic characterization of teeth and visual function in the published and new families reveals a consistent syndrome in all seven families, and all link or are consistent with linkage to 2q11, confirming the existence of a genetically homogenous condition that we now propose to call Jalili syndrome.

The cell adhesion molecule nectin-1 is critical for normal enamel formation in mice.

Nectin-1 is a member of a sub-family of immunoglobulin-like adhesion molecules and a component of adherens junctions. In the current study, we have shown that mice lacking nectin-1 exhibit defective enamel formation in their incisor teeth. Although the incisors of nectin-1-null mice were hypomineralized, the protein composition of the enamel matrix was unaltered.

2D mapping of texture and lattice parameters of dental enamel.

We have used synchrotron X-ray diffraction to study the texture and the change in lattice parameter as a function of position in a cross section of human dental enamel. Our study is the first to map changes in preferred orientation and lattice parameter as a function of position within enamel across a whole tooth section with such high resolution. Synchrotron X-ray diffraction with a micro-focused beam spot was used to collect two-dimensional (2D) diffraction images at 150 microm spatial resolution over the entire tooth crown.

Deformation and failure of cartilage in the tensile mode.

The aim of this study was to visualize, at the ultrastructural level, the deformation and failure mechanism of cartilage matrix in the tensile mode. Full-thickness dumbbell-shaped specimens were prepared from adult bovines. There were two specimen groups; in the 'parallel' group the specimen axis was parallel to the split lines defining the preferential orientation of the collagen in the articular surface, and in the 'perpendicular' group the specimen axis was perpendicular to the split lines.

Intracellular nanosphere subunit assembly as revealed by amelogenin molecular cross-linking studies.

Enamel matrix comprises nanospheres predominantly composed of amelogenin. Studies have shown that recombinant amelogenin forms nanospheres similar to those formed in vivo, but it is unclear exactly how nanospheres assemble in vivo. Are amelogenin monomers secreted into the enamel matrix where they then self-assemble to form nanospheres, or does nanosphere assembly actually occur intracellularly? The aim of this study was to attempt to answer this question.

Evidence for direct amelogenin-target cell interactions using dynamic force spectroscopy.

Increasing evidence suggests that amelogenin, long held to be a structural protein of developing enamel matrix, may also have cell signaling functions. However, a mechanism for amelogenin cell signaling has yet to be described. The aim of the present study was to use dynamic chemical force spectroscopy to measure amelogenin interactions with possible target cells.