Identification of novel genome-wide pleiotropic associations with oral inflammatory traits.

Oral inflammatory diseases (OIDs) are a group of dental diseases with multiple clinical manifestations that impact the majority of the world's population. Many studies have investigated the associations between individual OID traits and genomic variants, but whether pleiotropic loci are shared by oral inflammatory traits remains poorly understood. Here, we conducted multitrait joint analyses based on the summary statistics of genome-wide association studies (GWASs) of five dental traits from the UK Biobank. Among these genome-wide significant loci, two were novel for both painful gums and toothache. We identified causal variants at each novel locus, and functional annotation based on multiomics data suggested IL10 and IL12A/TRIM59 as potential candidate genes at the novel pleiotropic loci. Subsequent analyses of pathway enrichment and protein-protein interaction networks suggested the involvement of the candidate genes in immune regulation. In conclusion, our results uncover novel pleiotropic loci for OID traits and highlight the importance of immune regulation in the pathogenesis of OIDs. These findings will enhance our understanding of the pathogenesis of OIDs and be beneficial for risk screening, prevention, and the development of novel drugs targeting the immune regulation of OIDs.

Emerging role of exosomes in craniofacial and dental applications.

Exosomes, a specific subgroup of extracellular vesicles that are secreted by cells, have been recognized as important mediators of intercellular communication. They participate in a diverse range of physiological and pathological processes. Given the capability of exosomes to carry molecular cargos and transfer bioactive components, exosome-based disease diagnosis and therapeutics have been extensively studied over the past few decades. Herein, we highlight the emerging applications of exosomes as biomarkers and therapeutic agents in the craniofacial and dental field. Moreover, we discuss the current challenges and future perspectives of exosomes in clinical applications.

32 and you - genetic testing for dental disorders.

Genetic testing for serious illness and disease is becoming increasingly embedded in NHS healthcare. It can confirm a clinical diagnosis or guide therapy. Genetic testing for dental developmental disorders has moved beyond the realms of rarified grant-funded research groups and is now sufficiently rapid and affordable to be offered as part of a clinical service in some dental teaching hospitals. The first presentation of some genetic diseases may be in the dental surgery, so the family dentist should hone their diagnostic skills to identify patients who would benefit from referral to a genetics service. While diagnosis may sometimes guide treatment, there are now examples where it can even lead to cure. This article aims to describe some concepts and issues that a dentist should consider when referring for testing for a genetic dental disorder, and proposes that this subject area should be expanded in the dental undergraduate and postgraduate curricula in the UK.

Viral miRNAs Alter Host Cell miRNA Profiles and Modulate Innate Immune Responses.

Prevalence of the members of herpesvirus family in oral inflammatory diseases is increasingly acknowledged suggesting their likely role as an etiological factor. However, the underlying mechanisms remain obscure. In our recent miRNA profiling of healthy and diseased human tooth pulps, elevated expression of human herpesvirus encoded viral microRNAs (v-miRs) were identified. Based on the fold induction and significance values, we selected three v-miRs namely miR-K12-3-3p [Kaposi sarcoma-associated virus (KSHV)], miR-H1 [herpes simplex virus 1 (HSV1)], and miR-UL-70-3p [human cytomegalovirus (HCMV)] to further examine their impact on host cellular functions. We examined their impact on cellular miRNA profiles of primary human oral keratinocytes (HOK). Our results show differential expression of several host miRNAs in v-miR-transfected HOK. High levels of v-miRs were detected in exosomes derived from v-miR transfected HOK as well as the KSHV-infected cell lines. We show that HOK-derived exosomes release their contents into macrophages (Mφ) and alter expression of endogenous miRNAs. Concurrent expression analysis of precursor (pre)-miRNA and mature miRNA suggest transcriptional or posttranscriptional impact of v-miRs on the cellular miRNAs. Employing bioinformatics, we predicted several pathways targeted by deregulated cellular miRNAs that include cytoskeletal organization, endocytosis, and cellular signaling. We validated three novel targets of miR-K12-3-3p and miR-H1 that are involved in endocytic and intracellular trafficking pathways. To evaluate the functional consequence of this regulation, we performed phagocytic uptake of labeled bacteria and noticed significant attenuation in miR-H1 and miR-K12-3-3p but not miR-UL70-3p transfected primary human Mφ. Multiple cytokine analysis of E. coli challenged Mφ revealed marked reduction of secreted cytokine levels with important roles in innate and adaptive immune responses suggesting a role of v-miRs in immune subversion. Our findings reveal that oral disease associated v-miRs can dysregulate functions of key host cells that shape oral mucosal immunity thus exacerbating disease severity and progression.

Controversies in Oral and Maxillofacial Pathology.

Several benign pathologic entities that are commonly encountered by the oral and maxillofacial surgeon remain controversial. From etiology to treatment, no consensus exists in the literature regarding the best treatment of benign lesions, such as the keratocystic odontogenic tumor, giant cell lesion, or ameloblastoma. Given the need for often-morbid treatment to prevent recurrence of these lesions, multiple less-invasive treatments exist in the literature for each entity with little agreement. As the molecular and genomic pathogenesis of these lesions are better understood, directed treatments will hopefully lessen the contention in management.

[Heredity of orthodontic anomalies]. / Dedicnost ortodontických anomálií

The survey of most common orthodontic anomalies is given in this article. Authors, utilizing literature data, their own research as well as their therapeutic experience, try to elucidate the role of genetics in determination of dental anomalies and malocclusion. They emphasise the fact that genetically determined orthodontic anomalies are not easy to treat. Retention of treatment result could also be a problem. Occurrence of an anomaly in one member of the family should lead to the examination of other members, especially the young ones.

Candidate-gene exclusion in a family with inherited non-syndromic dental disorders.

OBJECTIVES: Amelogenesis imperfecta, dentinogenesis imperfecta, and dentin dysplasia are the most common non-syndromic dental disorders. In this study, we analysed and localised the gene(s) responsible for inherited non-syndromic dental disorders in a Chinese family. METHODS: This study identified and researched non-syndromic dental disorders in a four-generation Chinese family, including four affected individuals whose clinical phenotype was atypical. Linkage analysis with seven polymorphic markers that localise to six different autochromosomes showed that the family was linked through chromosome 4q. All exons and exon-intron boundaries of dentin sialophosphoprotein (DSPP), enamelin (ENAM), and ameloblastin (AMBN), which are located on chromosome 4q, were sequenced in nine of the family members. RESULTS: Direct DNA sequence analysis revealed the existence of a G to A transversion in exon 4 (g.13081786G>A, c.727G>A, p.Asp243Asn, based on reference sequences NM_014208.3) of the DSPP gene, and this sequence variation correlated exactly with the presence of the disease. CONCLUSION: These results indicate that mutation p.Asp243Asn is a highly probable cause of non-syndromic dental disorder in this Chinese family. The presence of symptom heterogeneity is possible, as the clinical classification system is hampered by the lack of close correlation between the subtype and the molecular defect.

SNP genome scanning localizes oto-dental syndrome to chromosome 11q13 and microdeletions at this locus implicate FGF3 in dental and inner-ear disease and FADD in ocular coloboma.

We ascertained three different families affected with oto-dental syndrome, a rare but severe autosomal-dominant craniofacial anomaly. All affected patients had the unique phenotype of grossly enlarged molar teeth (globodontia) segregating with a high-frequency sensorineural hearing loss. In addition, ocular coloboma segregated with disease in one family (oculo-oto-dental syndrome). A genome-wide scan was performed using the Affymetrix GeneChip10K 2.0 Array. Parametric linkage analysis gave a single LOD score peak of 3.9 identifying linkage to chromosome 11q13. Haplotype analysis revealed three obligatory recombination events defining a 4.8 Mb linked interval between D11S1889 and SNP rs2077955. Higher resolution mapping and Southern blot analysis in each family identified overlapping hemizygous microdeletions. SNP expression analysis and real-time quantitative RT-PCR in patient lymphoblast cell lines excluded a positional effect on the flanking genes ORAOV1, PPFIA1 and CTTN. The smallest 43 kb deletion resulted in the loss of only one gene, FGF3, which was also deleted in all other otodental families. These data suggest that FGF3 haploinsufficiency is likely to be the cause of otodental syndrome. In addition, the Fas-associated death domain (FADD) gene was also deleted in the one family segregating ocular coloboma. Spatiotemporal in situ hybridization in zebrafish embryos established for the first time that fadd is expressed during eye development. We therefore propose that FADD haploinsufficiency is likely to be responsible for ocular coloboma in this family. This study therefore implicates FGF3 and FADD in human craniofacial disease.

[PCR detection of periodontal bacteria and Streptococcus mutans in the biological samples from the oral cavity].

The paper describes an optimized technique for DNA isolation from the Streptococcus mutans cultures and from the clinical samples including proteinase K treatment and detergent lysis, followed by sorbent-based enrichment. This technique was employed for isolating DNA from the periodontal bacteria Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, and Bacteroides forsythus. A multiplex PCR technique was adapted for large-scale studies of clinical samples. An original PCR method was developed for the semiquantitative detection of Str. mutans, showing the sensitivity of 100 genome copies per reaction. Extensive studies of approximately 2,000 individuals have demonstrated that these methods are applicable to the study of the dental and gingival microflora in the biological sample from the oral cavity of persons with dental diseases from various age groups.

The impact of molecular genetics on oral health paradigms.

As a result of our increased understanding of the human genome, and the functional interrelationships of gene products with each other and with the environment, it is becoming increasingly evident that many human diseases are influenced by heritable alterations in the structure or function of genes. Significant advances in research methods and newly emerging partnerships between private and public sector interests are creating new possibilities for utilization of genetic information for the diagnosis and treatment of human diseases. The availability and application of genetic information to the understanding of normal and abnormal human growth and development are fundamentally changing the way we approach the study of human diseases. As a result, the issues and principles of medical genetics are coming to bear across all disciplines of health care. In this review, we discuss some of the potential applications of human molecular genetics for the diagnosis and treatment of oral diseases. This discussion is presented in the context of the ongoing technological advances and conceptual changes that are occurring in the field of medical genetics. To realize the promise of this new molecular genetics, we must be prepared to foresee the possibilities and to incorporate these newly emergent technologies into the evolving discipline of dentistry. By using examples of human conditions, we illustrate the broad application of this emerging technology to the study of simple as well as complex genetic diseases. Throughout this paper, we will use the following terminology: Penetrance--In a population, defined as the proportion of individuals possessing a disease-causing genotype who express the disease phenotype. When this proportion is less than 100%, the disease is said to have reduced or incomplete penetrance. Polymerase chain reaction (PCR)--A technique for amplifying a large number of copies of a specific DNA sequence flanked by two oligonucleotide primers. The DNA is alternately heated and cooled in the presence of DNA polymerase and free nucleotides, so that the specified DNA segment is denatured, hybridized with primers, and extended by DNA polymerase. MIM--Mendelian Inheritance in Man catalogue number from V. McKusick's Mendelian Inheritance in man (OMIM, 1998).

[Syndromes 18. Von Recklinghausen's disease]. / Syndromen 18. De ziekte van Von Recklinghausen.

Von Recklinghausen's disease (neurofibromatosis 1; NF1) is one of the neurofibromatoses and accounts for about 90% of all cases. Inheritance is autosomal dominant with about 30-50% of cases representing new mutations. Characteristic features for NF1 are six or more café-au-lait-spots, neurofibromas, Lisch nodules and axillary freckling. Oral manifestation consists of neurofibromas and intrabony lesions. Due to growth of the oral and facial neurofibromas maldevelopment of the facial skeleton and malocclusion are seen. Surgical correction in young individuals easily leads to recurrence. Contour corrected surgery in grown up individuals is possible.

Mapping X-linked ophthalmic diseases. IV. Provisional assignment of the locus for X-linked congenital cataracts and microcornea (the Nance-Horan syndrome) to Xp22.2-p22.3.

The Nance-Horan syndrome (NHS) is an infrequent X-linked disorder typified by dense congenital central cataracts, microcornea, anteverted and simplex pinnae, brachymetacarpalia, and numerous dental anomalies. The regional location of the genetic mutation causing NHS is unknown. The authors applied the modern molecular techniques of analysis of restriction fragment length polymorphisms to five multigenerational kindreds in which NHS segregated. Provisional linkage is established to two DNA markers--DXS143 at Xp22.3-p22.2 and DXS43 at Xp22.2. Regional localization of NHS will provide potential antenatal diagnosis in families at risk for the disease and will enhance understanding of the multifaceted genetic defects.

[Focal dermal hypoplasia (Goltz's syndrome). Review of the literature and clinical contribution]. / Ipoplasia focale dermica (sindrome di Goltz). Revisione della letteratura e contributo clinico.

A clinical case of focal dermal hypoplasia or Goltz syndrome is described with details of the odontostomatological features both generally encountered and observed in the present case. The main aetiopathogenic hypotheses are also discussed and a dominant X-linked transmission is postulated.