Metabolic Syndrome: A Family Affair

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Science Translational Medicine  04 Jun 2014:
Vol. 6, Issue 239, pp. 239ec96
DOI: 10.1126/scitranslmed.3009414

A cluster of heritable traits known as the metabolic syndrome (central obesity, dyslipidemia, hypertension, and insulin resistance) is a major predisposing factor for coronary artery disease, a leading cause of death worldwide. Yet, human genetic abnormalities that cause the multiple features of metabolic syndrome have not been identified. Discovering genetic causes of metabolic syndrome, particularly variants that produce large phenotypic effects, could point to previously unknown disease mechanisms and inform new therapies for cardiovascular disease.

Keramati et al. identified three families from southwestern Iran with an unusual constellation of phenotypes resembling an extreme form of early-onset metabolic syndrome with an autosomal-dominant inheritance pattern. Linkage analysis and whole-exome sequencing of family members identified a founder mutation in the DYRK1B gene in which cysteine was substituted for arginine at position 102 (R102C) in a highly conserved kinase-like domain. The R102C mutation precisely cosegregated with the clinical syndrome in all affected family members and was absent in unaffected family members and unrelated control subjects. DYRK1B is a ubiquitously expressed protein kinase that is known to be induced during adipogenesis and repress Sonic hedgehog (SHH)–Wnt signaling. Because the SHH-Wnt pathway functions as a negative regulator of adipogenesis, the authors hypothesized that DYRK1B was proadipogenic. When compared with the nonmutant form of DYRK1B, Keramati and colleagues demonstrated that the R102C mutant caused increased adipogenic differentiation and expression of a key gluconeogenic enzyme in vitro, suggesting a gain-of-function effect for this mutant protein. Interestingly, screening a population of unrelated white patients with metabolic syndrome identified a family with a second previously undiscovered mutation in DYRK1B (H90P) that also cosegregated with disease phenotype, displayed autosomal dominant inheritance, and encoded a mutant protein with gain-of-function features. Whether these DYRK1B mutations cause human metabolic syndrome by promoting adipogenesis (fat formation) or gluconeogenesis (glucose production) remains unknown.

This study demonstrates that identification of rare genetic variants with moderate-to-large phenotypic effects can provide a better understanding of metabolic syndrome pathogenesis and its link to cardiovascular risk. Now, researchers can continue to unravel how aberrant DYRK1B function leads to metabolic syndrome, knowledge that might create novel preventative and therapeutic strategies for cardiometabolic disease.

A. R. Keramati et al., A form of the metabolic syndrome associated with mutations in DYRK1B. N. Engl. J. Med. 370, 1909–1919 (2014). [PubMed]

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