The DSPP gene regulates dentin mineralisation, and its pathogenic variants cause a spectrum of defects ranging from dentin dysplasia (DD-II) to dentinogenesis imperfecta (DGI-II/III). Clinical variability often confounds diagnosis. This systematic review of 48 publications (70 variants, 99 records) delineates quantitative genotype-phenotype correlations. Results revealed distinct molecular clustering: Exon 5 harboured 61 % of variants, predominantly frameshifts disrupting the repetitive dentin phosphoprotein (DPP) domain. In contrast, upstream regions (exons 2-4) contained mixed variant types affecting the signal peptide and dentin sialoprotein (DSP). Statistical analysis established a definitive severity gradient. Exon 5 frameshifts were significantly associated with the milder DD-II, characterised by thistle-shaped pulps and clinically normal permanent dentition. Conversely, upstream signal peptide, splice site, and missense variants (exons 2-3) were linked to the severe DGI-III, manifesting as 'shell teeth', rapid attrition, and pulp exposure requiring complex prosthodontic intervention. DGI-II displayed no specific genomic clustering, representing an intermediate phenotype. These findings provide complementary insights to historical classifications, highlighting a continuous spectrum of DSPP disorders where upstream defects cause severe failure, while downstream defects result in attenuated localised anomalies. Consequently, integrating DSPP genotyping into diagnostic workflows is essential to predict disease progression, refine molecular taxonomy beyond the Shields system, and guide personalised rehabilitation.

Variants in the dentin sialophosphoprotein (DSPP) gene are associated with dentin dysplasia type II (DD-II; OMIM # 125420) and dentinogenesis imperfecta (DI) types II (OMIM # 125490) and III (OMIM # 125500). DSPP encodes a precursor protein cleaved into three dentin matrix proteins: dentin sialoprotein (DSP), dentin phosphoprotein/phosphophoryn (DPP) and dentin glycoprotein (DGP). Exon 5 contains over 200 tandem 9-base pair repeats (DSS domain), complicating sequencing with standard methods. We studied 112 individuals (42 index cases and 70 relatives) with clinical signs of DI or DD. DNA extracted from saliva was analysed using the GenoDENT next-generation sequencing panel. For inconclusive cases, long-range PCR and Oxford Nanopore Technology (ONT) long-read sequencing were used to overcome limitations in analysing the repetitive DSPP region. Pathogenic or likely pathogenic DSPP variants were identified in 41 families, including 8 known and 14 novel variants. Most were in exon 5, causing frameshifts resulting in a -1 reading-frame shift with a hydrophobic C-terminal extension and termination at a downstream stop codon. ONT sequencing enabled detection in cases where short-read methods failed. Several variants showed familial segregation and variable expressivity. This study demonstrates the value of long-read sequencing to resolve complex DSPP regions and expands the variant spectrum. The variability in clinical presentation suggests the influence of modifier factors, warranting further genotype-phenotype studies.

To investigate the clinical characteristics and genetic etiology of a Chinese pedigree affected with Hereditary dentin dysplasia type II (DD-II) due to variant of dentin sialophosphoprotein (DSPP) gene. A child diagnosed with DD- II at the Third Clinical Division of Peking University Hospital of Stomatology in December 2021 and her family members were selected as study subjects. Clinical data were retrospectively analyzed. Saliva samples were collected from the proband, her parents and sister for genomic DNA extraction. Whole exome sequencing (WES) was carried out. Candidate variant was verified by Sanger sequencing and TOPO-TA cloning sequencing. The candidate variant was also subjected to bioinformatics analysis using Mutation Taster v2021. Secondary and tertiary structures of the wild-type and variant DSPP proteins were predicted with psipred v4.0 and PyMOL v2.3 software, respectively. The pathogenicity of the variant was classified based on the guidelines from American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Peking University Hospital of Stomatology (Ethics No.: PKUSSIRB-202162021). The proband and her mother and sister had all exhibited typical clinical manifestations of hereditary DD-II. The primary dentition of the proband displayed yellowish brown discoloration, wear, and obliteration in the chamber and root canal, while the permanent teeth of the proband's sister and mother appeared nearly normal in both color and appearance, though with obliteration in the chamber and root canal. Her father showed normal dentition. WES identified a heterozygous c.1915_1918delAAGT, p.(Lys639Glnfs*674) frameshift variant in the DSPP gene. Sanger sequencing and TOPO-TA cloning sequencing confirmed the presence of this variant in the proband, the proband's sister, and the mother, while the proband's father was negative for the variant, indicating an autosomal dominant inheritance pattern. The variant was predicted to be pathogenic by Mutation Taster v2021. Prediction of the secondary structure of the DSPP protein showed that the variant has changed it from coil to helix. The tertiary structure prediction of the DSPP protein showed change of the spatial structure of the variant DSPP, with the loops in the variant region replaced by helices at multiple sites. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+PM2_Supporting+PP1+PP4). Phenotypic analysis and genetic testing of this family has clarified the clinical diagnosis of hereditary DD- II. The c.1915_1918delAAGT variant probably underlay the pathogenesis of DD-II in this family. Above results have expanded the phenotypic spectrum of the disease and may contribute to further clinical and genetic research on this disease.

Odontodysplasia is a dental anomaly that affects the maturation and formation of teeth, resulting in hypoplasia and hypocalcification of both enamel and dentin. It can affect one or several quadrants of the dentition, although generalized involvement is extremely rare. The exact cause is unclear, but trauma, infection, and nutritional or metabolic deficiencies have been suggested as possible contributing factors. Diagnosis requires a combination of clinical and radiological findings. Clinically, it presents as small teeth with yellow or brown discoloration, and it can affect both the primary and permanent dentition. Radiographically, there is reduced radiodensity, giving rise to a blurred or "ghost tooth" appearance. Histologically, these teeth show aprismatic enamel, interglobular dentin, and the presence of enamel-like calcifications known as enameloid conglomerates. Treatment depends on the extent of tooth involvement and the patient's age. This paper reports the case of a 31-year-old woman who presented with this rare anomaly in its generalized form, making her the oldest patient with this diagnosis reported in the literature.

tRNA N7-methylguanosine (m7G) is one of the most abundant epigenetic modifications in mammals, which is catalyzed by the methyltransferase 1-WD repeat-containing protein 4 (METTL1-WDR4) complex. Missense mutations in WDR4 have been linked to primordial dwarfism, which shows severe craniofacial developmental deformities including small teeth, but the underlying molecular mechanisms remain elusive. In this study, we explore the effect of m7G modification on dentin formation during tooth root development. METTL1 was actively expressed in mice developing tooth roots, and its expression became undetectable after tooth root formation. Next, we generated Prrx1-Cre driven Mettl1 (Prrx1Cre;Mettl1fl/fl) conditional KO mice to delete Mettl1 in dental mesenchyme and explored its regulation during tooth development. Micro-computed tomography revealed that the roots of the mandibular first molar in Prrx1Cre;Mettl1fl/fl mice were shorter and smaller compared to littermate control, with a reduction in the width of dentin and pre-dentin in both the root area and the crown area. Wdr4R215L/R215L mice also exhibited tooth root shortening and dentin thinning, phenocopying the Prrx1Cre;Mettl1fl/fl mice. Moreover, METTL1-depleted human dental pulp cells (hDPCs) showed decreased ability of proliferation, migration, and odontogenic differentiation. RNA-seq revealed upregulation of the p53 signaling pathway and cell cycle arrest after deletion of Mettl1. The proliferation and odontogenic differentiation of METTL1-depleted hDPCs is partially rescued with pifithrin-α (PFT-α), a p53 signaling inhibitor. Taken together, our results demonstrate that loss of METTL1-mediated tRNA m7G modification impairs the proliferation and odontogenic differentiation of hDPCs via the p53 signaling pathway and affects the dentin formation during tooth root development, providing a novel epigenetic mechanism underlying small teeth. This study explores how the tRNA N7-methylguanosine, an essential epigenetic modification, influences tooth root development, particularly the dentin formation. Researchers focused on a protein complex, METTL1-WDR4, responsible for this modification. They found that mice genetically engineered to lack METTL1 developed shorter roots and thinner pre-dentin/dentin layer, which is similar to patients with mutations in the related WDR4 gene. Experiments using human dental cells showed that silencing METTL1 reduced their ability to grow, move, and mature into dentin-producing cells. This problem was linked to overactivation of the p53 signaling pathway, which slows cell growth. Blocking this pathway partially restored normal cell function. The findings reveal a new mechanism—controlled by tRNA N7-methylguanosine—that regulates tooth root and dentin formation, offering insights into why certain genetic mutations cause dental defects.