A Form of Metabolic Syndrome Associated with Mutations in DYRK1B
Jeffrey Ma
Introduction
Metabolic Syndrome
Leading cause of death worldwide
Symptoms increase risk of heart disease, stroke, and diabetes
Inheritable risk factors that is known as metabolic syndrome early-onset coronary artery disease central obesity hypertension diabetes http://www.tolwellness.com/wp-content/uploads/2014/03/metabolic_syndrome.jpg Single gene mutations produce these risk factors of this syndrome (Mani, Rhadakrishnan, Wang et al. 2007)
Genetic analysis
Successful in identifying causative mutations
Limited in mapping susceptibility of genes for clusters of cardiovascular risk traits
Next generation sequencing
Identification of rare variants in outlier populations
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DYRK1B R102C displayed the most activity in levels of G6pase also displayed higher rate of messenger RNA for G6pase
Independent variables: Vector, DYRK1B NM, DYRK1B R102C
Dependent variables: G6pase Promoter Activity Assayed by Luciferase (RIU), Factor Change in mRNA Levels of G6pase
Control: Vector
Panel C
R102C variant expressed the highest amount of G6pase in HepG2 cells
This function is independent of the kinase
Independent variables: Vector, DYRK1B NM, DYRK1B R102C, kinase-defective DYRK1B
Dependent variables: DYRK1B, G6pase, beta-Actin
Control: Vector
Panel D shows the dose effect of NM DYRK1B on endogenous G6pase
Independent variables: dose effect of DYRK1B NM
Dependent variables: DYRK1B, G6pase, beta-Actin
Control: 0.0 micrograms
Discussion
Establishes an association between traits of metabolic syndrome and DYRK1B R102C
Proves hypothesis to be correct
The metabolic syndrome is the result of a mutation on a single gene
Mutation alters two important functions of the protein
Adipocyte differentiation
DYRK1B involvement in adipogenesis
Enhance adipogenesis by inhibiting SHH or increase turnover in p27Kip
Deficiency leads to obesity and insulin resistance
R102C affects p27Kip turnover
The mutation decreases Gli-2 which increases