Abdominal Obesity-Metabolic Syndrome 3

A number sign (#) is used with this entry because of evidence that abdominal obesity-metabolic syndrome-3 (AOMS3) is caused by heterozygous mutation in the DYRK1B gene (604556) on chromosome 19q13.

For a general phenotypic description and a discussion of genetic heterogeneity of abdominal obesity-metabolic syndrome, see 605552.

Clinical Features

Keramati et al. (2014) studied 3 large multigenerational families from a community in southwest Iran in which 25 affected members had early-onset myocardial infarction or coronary artery disease as well as central obesity, type 2 diabetes, and hypertension, a constellation of features that met the standard definition of metabolic syndrome. Central obesity was of juvenile onset, and all 25 affected family members had early-onset myocardial infarction or coronary artery disease at a mean age of 44 years. The presence of central obesity, type 2 diabetes, and hypertension was not explained by neurohormonal activation. Among the affected individuals, 3 had stroke and there were 3 sudden deaths. The families were considered to be outliers because of the low prevalence of early-onset coronary artery disease and obesity in the local community.

Mapping

Keramati et al. (2014) performed genomewide multipoint parametric analysis in 3 multigenerational Iranian families with metabolic syndrome and early-onset coronary artery disease and obtained a maximum multipoint lod score of 5.27 for coronary artery disease to a small segment of chromosome 19q13; the lod score rose to 6.34 in the analysis of both affected and unaffected family members. Separate analysis of the 19q13 region with central obesity, hypertension, and type 2 diabetes showed similar results. Haplotype analysis showed that all 3 families shared identical markers spanning a 6.1-Mbp haplotype flanked by the SNPs rs833917 and rs4801170. Haplotype sharing among the families was indicative of their common ancestral origin and suggested the presence of a founder mutation.

Molecular Genetics

Keramati et al. (2014) performed whole-exome sequencing in the probands from 2 of 3 multigenerational Iranian families with metabolic syndrome and early-onset coronary artery disease and identified a heterozygous missense mutation in the DYRK1B gene (R102C; 604556.0001) that segregated with disease in all 3 families. The mutation was not found in 2,000 ethnically matched Iranian controls, in 3,600 Caucasian controls from the United States, or in several exome databases. Functional characterization showed gain of function with the R102C allele. Analysis of the DYRK1B gene in 300 morbidly obese Caucasian individuals with coronary artery disease and multiple metabolic phenotypes identified heterozygosity for another missense mutation (H90P; 604556.0002) in 5 unrelated patients. DNA samples from family members of 1 of the patients showed a consistent pattern of cosegregation of the mutation with features of metabolic syndrome in an autosomal dominant fashion. Five members of the family had died from myocardial infarction between 50 and 60 years of age.

He et al. (2014) noted that the R102C mutation induces increased expression of PPARG (601487) and PGC1A (604517), which are associated with plasma levels of adipokines that play crucial roles in the metabolic syndrome, including adiponectin (605441), leptin (164160), resistin (605565), and FGF21 (609436). The authors suggested that adipokines might serve as plasma biomarkers for this form of the metabolic syndrome.

Using electronic medical records of 7,800 participants in the Geisinger MyCode Project, Mirshahi et al. (2014) performed a 'phenomewide' association study involving an L28P variant of DYRK1B predicted to be damaging, and found a significant protective effect of L28P in 42 heterozygotes against type 2 diabetes (p = 0.002) as well as a trend toward a protective effect against hypertension. They concluded that some DYRK1B variants are associated with autosomal dominant protective effects.