Mutation in SSUH2 Causes Autosomal-Dominant Dentin Dysplasia Type I.

Dentin dysplasia type I (DDI) is an autosomal-dominant genetic disorder resulting from dentin defects. The molecular basis of DDI remains unclear. DDI exhibits unique characteristics with phenotypes featuring obliteration of pulp chambers and diminutive root, thus providing a useful model for understanding the genetics of tooth formation. Using a large Chinese family with 14 DDI patients, we mapped the gene locus responsible for DDI to 3p26.1-3p24.3 and further identified a missense mutation, c.353C>A (p.P118Q) in the SSUH2 gene on 3p26.1, which co-segregated with DDI. We showed that SSUH2 (p.P118Q) perturbed the structure and significantly reduced levels of mutant (MT) protein and mRNA compared with wild-type SSUH2. Furthermore, MT P141Q knock-in mice (+/- and -/-) had a unique partial obliteration of the pulp cavity and upregulation or downregulation of six major genes involved in odontogenesis: Dspp, Dmp1, Runx2, Pax9, Bmp2, and Dlx2. The phenotype of missing teeth was determined in zebrafish with morpholino gene knockdowns and rescued by injection of normal human mRNA. Taken together, our observations demonstrate that SSUH2 disrupts dental formation and that this novel gene, together with other odontogenesis genes, is involved in tooth development.

A splicing mutation in VPS4B causes dentin dysplasia I.

BACKGROUND: Dentin dysplasia I (DDI) is a genetically heterogeneous autosomal-dominant disorder characterised by rootless teeth with abnormal pulpal morphology, the aetiology of which presents as genetically heterogeneous. METHODS AND RESULTS: Using a cohort of a large Chinese family with 10 patients with DDI, we mapped to a 9.63 Mb candidate region for DDI on chromosome 18q21.2-q21.33. We then identified a mutation IVS7+46C>G which resulted in a novel donor splice site in intron 7 of the VPS4B gene with co-segregation of all 10 affected individuals in this family. The aberrant transcripts encompassing a new insert of 45 bp in size were detected in gingival cells from affected individuals. Protein structure prediction showed that a 15-amino acid insertion altered the ATP-binding cassette of VPS4B. The mutation resulted in significantly reduced expression of mRNA and protein and altered subcellular localisation of VPS4B, indicating a loss of function of VPS4B. Using human gingival fibroblasts, the VPS4B gene was found to act as an upstream transducer linked to Wnt/ß-catenin signalling and regulating odontogenesis. Furthermore, knockdown of vps4b in zebrafish recapitulated the reduction of tooth size and absence of teeth similar to the tooth phenotype exhibited in DDI index cases, and the zebrafish mutant phenotype could be partially rescued by wild-type human VPS4B mRNA. We also observed that vps4b depletion in the zebrafish negatively regulates the expression of some major genes involved in odontogenesis. CONCLUSIONS: This study identifies VPS4B as a disease-causing gene for DDI, which is one of the important contributors to tooth formation, through the Wnt/ß-catenin signalling pathway.

Mechanism of transverse fracture of the skull base caused by blunt force to the mandible.

Transverse fracture of the skull base is common both in the crushing of temporal regions of the skull and in the case of force acting on one temporal region. However, the mechanism of transverse skull base fracture caused by maxillofacial force has not been fully clarified. To provide an injury identification basis for forensic pathologists and clinicians, this paper combines accident reconstruction and finite element analysis methods to study the injury mechanism of an incomplete transverse fracture of skull base after the injured individual's mandible was subjected to violence in a traffic accident. The results show that after the injured individual's mandible was subjected to violence, forces in the direction of the left mandibular fossa and the right mandibular fossa were generated, creating the component forces. The combination of the two forces can produce a crushing effect toward the center of the skull base, as if the left and right temporal regions are being crushed, and the stress is concentrated at the joint of the mandible, the middle cranial fossa and the hypophyseal fossa. When the stress exceeds a certain limit, it will cause a transverse fracture of the skull base.

An acute fatality from suicidal caustic soda ingestion complicated by stab wound penetrating the stomach.

Acute death from caustic ingestion is uncommon. We report an autopsy case of acute fatality from suicidal ingestion of a liquid caustic soda solution with peritoneal leakage due to a stab wound to the stomach. The victim was a 58-year-old man, who died about 1 h after being transported to a hospital emergency care unit. There were corrosive erosions around the mouth and a stab wound in the lower chest. The tongue, pharynx, larynx, esophagus, stomach and the proximal portion of the duodenum were all eroded and edematous. The stab wound perforated the diaphragm and stomach, accompanied by liquefactive corrosion in the left-lower thoracic and left-upper peritoneal cavities. There was a marked elevation of the postmortem serum sodium concentration and alkalosis. The observations suggested peritoneal absorption of leaked caustic soda solution, which may have greatly contributed to the acute fatality despite an intensive clinical life support.