Results:

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.