A form of the metabolic syndrome associated with mutations in DYRK1B

  • Posted on: 26 March 2015
  • By: fcoldren
TitleA form of the metabolic syndrome associated with mutations in DYRK1B
Publication TypeJournal Article
Year of Publication2014
AuthorsKeramati AR, Fathzadeh M, Go G-W, Singh R, Choi M, Faramarzi S, Mane S, Kasaei M, Sarajzadeh-Fard K, Hwa J, Kidd KK, Bigi MABabaee, Malekzadeh R, Hosseinian A, Babaei M, Lifton RP, Mani A
JournalN Engl J Med
Date Published2014 May 15
KeywordsCoronary Artery Disease, Diabetes Mellitus, Type 2, Exome, Female, Founder Effect, Genetic Linkage, Genetic Predisposition to Disease, Glucose-6-Phosphatase, Humans, Hypertension, Male, Metabolic Syndrome X, Mutation, Obesity, Abdominal, Pedigree, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases

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.).

Alternate JournalN. Engl. J. Med.
PubMed ID24827035
PubMed Central IDPMC4069260
Grant List5U54HG006504 / HG / NHGRI NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
R01 HL094574 / HL / NHLBI NIH HHS / United States
R01 HL094784 / HL / NHLBI NIH HHS / United States
R01 HL115247 / HL / NHLBI NIH HHS / United States
R01HL094574-03 / HL / NHLBI NIH HHS / United States
R01HL094784-01 / HL / NHLBI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
U54 HL117798 / HL / NHLBI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States