A form of the metabolic syndrome associated with mutations in DYRK1B.
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-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.


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.).
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Ali R
AR
Keramati
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Mohsen
M
Fathzadeh
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Gwang-Woong
GW
Go
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Rajvir
R
Singh
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Murim
M
Choi
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Saeed
S
Faramarzi
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Shrikant
S
Mane
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Mohammad
M
Kasaei
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Kazem
K
Sarajzadeh-Fard
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
John
J
Hwa
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Kenneth K
KK
Kidd
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Mohammad A
MA
Babaee Bigi
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Reza
R
Malekzadeh
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Adallat
A
Hosseinian
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Masoud
M
Babaei
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Richard P
RP
Lifton
Department of Internal Medicine, Yale Cardiovascular Research Center (A.R.K., M.F., G.-W.G., R.S., S.F., J.H., A.M.), Yale Center for Mendelian Genomics (M.C., S.M., R.P.L., A.M.), Department of Genetics (K.K.K., R.P.L., A.M.), and Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, CT; the Digestive Disease Research Institute, Shariati Hospital (M.F., K.S.-F., R.M.), and Department of Medical Genetics (M.F.), Tehran University of Medical Sciences, Tehran, the Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz (M.K., K.S.-F., M.A.B.B.), and Ardabil University of Medical Sciences, Ardabil (A.H., M.B.) - all in Iran.
Arya
A
Mani
D003324:Coronary Artery Disease / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D059472:Exome; D005260:Female; D018703:Founder Effect; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D009154:Mutation; D056128:Obesity, Abdominal / Q000235:genetics; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D000097603:Dyrk Kinases
D005952:Glucose-6-Phosphatase; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases