When is it MODY? Challenges in the Interpretation of Sequence Variants in MODY Genes

The genomics revolution has raised more questions than it has provided answers. Big data from large population-scale resequencing studies are increasingly deconstructing classic notions of Mendelian disease genetics, which support a simplistic correlation between mutational severity and phenotypic outcome. The boundaries are being blurred as the body of evidence showing monogenic disease-causing alleles in healthy genomes, and in the genomes of individuals with increased common complex disease risk, continues to grow. In this review, we focus on the newly emerging challenges which pertain to the interpretation of sequence variants in genes implicated in the pathogenesis of maturity onset diabetes of the young (MODY), a presumed monogenic form of diabetes characterized by Mendelian inheritance. These challenges highlight the complexities surrounding the assignments of pathogenicity, in particular to rare protein-alerting variants, and bring to the forefront some profound clinical diagnostic implications. As MODY is both genetically and clinically heterogeneous, an accurate molecular diagnosis and cautious extrapolation of sequence data are critical to effective disease management and treatment. The biological and translational value of sequence information can only be attained by adopting a multitude of confirmatory analyses, which interrogate variant implication in disease from every possible angle. Indeed, studies which have effectively detected rare damaging variants in known MODY genes in normoglycemic individuals question the existence of a single gene mutation scenario: does monogenic diabetes exist when the genetic culprits of MODY have been systematically identified in individuals without MODY

AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease

Objective: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Steroid hormones and bile acids are potent regulators of hepatic carbohydrate and lipid metabolism. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyzes a fundamental step in bile acid synthesis.Methods: Human liver biopsies were obtained from 34 obese patients and AKR1D1 mRNA expression levels were measured using qPCR. Genetic manipulation of AKR1D1 was performed in human HepG2 and Huh7 liver cell lines. Metabolic assessments were made using transcriptome analysis, western blotting, mass spectrometry, clinical biochemistry, and enzyme immunoassays.Results: In human liver biopsies, AKR1D1 expression decreased with advancing steatosis, fibrosis and inflammation. Expression was decreased in patients with type 2 diabetes. In human liver cell lines, AKR1D1 knockdown decreased primary bile acid biosynthesis and steroid hormone clearance. RNA-sequencing identified disruption of key metabolic pathways, including insulin action and fatty acid metabolism. AKR1D1 knockdown increased hepatocyte triglyceride accumulation, insulin sensitivity, and glycogen synthesis, through increased de novo lipogenesis and decreased β-oxidation, fueling hepatocyte inflammation. Pharmacological manipulation of bile acid receptor activation prevented the induction of lipogenic and carbohydrate genes, suggesting that the observed metabolic phenotype is driven through bile acid rather than steroid hormone availability.Conclusions: Genetic manipulation of AKR1D1 regulates the metabolic phenotype of human hepatoma cell lines, driving steatosis and inflammation. Taken together, the observation that AKR1D1 mRNA is down-regulated with advancing NAFLD suggests that it may have a crucial role in the pathogenesis and progression of the disease.<br/

Risk of Postoperative Sensitivity and Pulpal Complications in Respect of: Amount of Reduction, Temporization, Cement Type

Fixed partial dentures (FPDs) made of metal ceramic are a popular treatment option for missing teeth. Studies have shown that posterior abutments of FPDs had a higher pulp survival rate than anterior abutments. Postoperative sensitivity following the cementation of a fixed prosthesis is a frequent symptom, especially when the abutments include important pulp. Dentinal hypersensitivity affects between 4 and 74 percent of people. Females are found to have a somewhat greater DH incidence than males. While DH can affect individuals of any age, there have been several theories on what causes abutment sensitivity after tooth preparation and cementation. In this review we included some of it. Also, we discussed methods of management of postoperative sensitivity and Management of fractured abutment screw.</jats:p