A Form of the Metabolic Syndrome Associated With Mutations in DYRK1B

Study Questions:

Are there specific genetic mutations associated with the metabolic syndrome?


Three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes were identified. Linkage analysis and whole-exome sequencing were used to identify the disease-causing gene associated with the metabolic syndrome.


The clinically characterized members of the three study families included 25 affected family members, 12 unaffected family members, and 2 family members with clinical features of the metabolic syndrome, but with unknown status with respect to coronary artery disease. All 25 affected family members had early-onset myocardial infarction or coronary artery disease at a mean age of 44.8 years in men and 44.2 years in women. Additional clinical features included central obesity, type 2 diabetes, and hypertension. The constellation of medical conditions in all of the affected family members (and none of the unaffected family members) met the standard definition of the metabolic syndrome, according to the criteria of the National Cholesterol Education Program of the National Institutes of Health. A founder mutation was identified in DYRK1B, substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain. The mutation precisely cosegregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Functional characterization of the disease gene revealed that nonmutant protein encoded by DYRK1B inhibits the signaling pathways and consequently enhances adipogenesis. Furthermore, DYRK1B promoted the expression of the key gluconeogenic enzyme glucose-6-phosphatase. The R102C allele showed gain-of-function activities by potentiating these effects. A second mutation, substituting proline for histidine 90, was found to cosegregate with a similar clinical syndrome in an ethnically distinct family.


The investigators concluded that these findings indicate a role for DYRK1B in adipogenesis and glucose homeostasis, and associate its altered function with an inherited form of the metabolic syndrome.


These results suggest potential for genetic testing and possible therapies that modify factors related to the development of the metabolic syndrome, including adipogenesis and glucose control.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Hypertension

Keywords: Obesity, Abdominal, Myocardial Infarction, Coronary Artery Disease, Diabetes Mellitus, Type 2, Glucose-6-Phosphatase, Adipogenesis, Genetic Testing, Glucose, Metabolic Syndrome X, Mutation, Cholesterol, National Institutes of Health (U.S.), Homeostasis, Hypertension

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