A Form of the Metabolic Syndrome Associated with Mutations inDYRK1B

Abstract

BACKGROUND Genetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome. METHODS We identified three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes. We used linkage analysis and whole-exome sequencing to identify the disease-causing gene. RESULTS 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 SHH (sonic hedgehog) and Wnt signaling pathways and consequently enhances adipogenesis. Furthermore, DYRK1B promoted the expression of the key gluconeogenic enzyme glucose-6-phosphatase. The R102C allele showed gain-offunction 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. CONCLUSIONS 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. (Funded by the National Institutes of Health.)

Genetics: Implications for Prevention and Management of Coronary Artery Disease

“…For many of these families identified to date, the culprit mutation has proved to be a highly damaging mutation within a gene that strongly influences circulating low-density lipoprotein (LDL) cholesterol levels (e.g., familial hypercholesterolemia (FH) genes, including LDLR, APOB, PCSK9, and, less commonly, LDLRAP1, ABCG5, and ABCG8) (29). In more recent studies, the culprit mutation has been found in genes predisposing to severe forms of the metabolic syndrome (e.g., LRP6, DYRK1B) (30,31). The initial observation that supported the highly multigenic nature of CAD for a majority of subjects presenting with CAD was the failure of linkage studies performed on families with a more typical low penetrance of disease to detect any susceptibly loci (29,32).…”

Translational Research Methods: Basics of Renal Molecular Biology

“…By selectively capturing the exons of the nearly 20,000 human genes, which constitute about 1-2 % of the euchromatic DNA, it is possible to sequence at high coverage (60-90X) the entire protein coding region of the genome at a cost of $600-800 per sample. This approach has been tremendously efficient in solving the molecular diagnosis of a multitude of Mendelian and complex traits [9][10][11][12][13][14][15][16][17][18][19][20][21]. The possibility of performing rapid diagnosis for known genetic causes for Mendelian diseases led to the development of array-based targeted gene panels for diseases (or group of diseases) to use in the clinical settings.…”

Unraveling New Therapeutic Targets of Coronary Artery Disease by Genetic Approaches

“…Another study by Keramati et al also used the same method to identify a founder mutation of DYRK1B in 3 large families with coinheritance of early-onset CAD, central obesity, hypertension, and diabetes. 23 These pioneering studies highlight the opportunities of applying NGS to severely affected families to identify new mechanism of the disease and thereby new therapeutic targets.…”