ClinVar

In 3 multigenerational Iranian families segregating autosomal dominant abdominal obesity-metabolic syndrome (AOMS3; 615812) and early-onset coronary artery disease, Keramati et al. (2014) identified a heterozygous c.304C-T transition in the DYRK1B gene, resulting in an arg102-to-cys (R102C) substitution at a highly conserved residue in the kinase-like domain. The mutation, which segregated completely with disease in all 3 families, was not found in 2,000 ethnically matched Iranian controls or 3,600 Caucasian controls from the United States, or in samples from 2,500 individuals in the Allele Frequency Database, 5,000 exomes from the Yale Center for Genome Analysis database, or 5,400 exomes in the NHLBI ESP5400 database. Functional analysis of transfected 3T3-L1 cells showed that accumulation of intracellular lipid was significantly greater with R102C than wildtype DYRK1B, and cells expressing the R102C variant were able to transform into mature adipocytes without requiring adipogenic medium. Expression levels of CEBPA (116897), PPARG (601487) isoforms 1 and 2, and PGC1A (PPARGC1A; 604517) were higher, and those of GLI1 (165220) and p27(KIP1) (CDKN1B; 600778) were lower in cells transfected with the R102C mutant compared to wildtype. In addition, WNT (see 164820) signaling activity was lower in mutant cells compared to wildtype.