Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum

Abstract

Background We investigated pathogenic DYRK1B variants causative of abdominal obesity-metabolic syndrome 3 (AOMS3) in a group of patients originally diagnosed with type 2 diabetes. All DYRK1B exons were analyzed in a sample of 509 unrelated adults with type 2 diabetes and 459 controls, all belonging to the DMS1 SIGMA-cohort (ExAC). We performed in silico analysis on missense variants using Variant Effect Predictor software. To evaluate co-segregation, predicted pathogenic variants were genotyped in other family members. We performed molecular dynamics analysis for the co-segregating variants. Results After filtering, Mendelian genotypes were confirmed in two probands bearing two novel variants, p.Arg252His and p.Lys68Gln. Both variants co-segregated with the AOMS3 phenotype in classic dominant autosomal inheritance with full penetrance. In silico analysis revealed impairment of the DYRK1B protein function by both variants. For the first time, we describe age-dependent variable expressivity of this entity, with central obesity and insulin resistance apparent in childhood; morbid obesity, severe hypertriglyceridemia, and labile type 2 diabetes appearing before 40 years of age; and hypertension emerging in the fifth decade of life. We also report the two youngest individuals suffering from AOMS3. Conclusions Monogenic forms of metabolic diseases could be misdiagnosed and should be suspected in families with several affected members and early-onset metabolic phenotypes that are difficult to control. Early diagnostic strategies and medical interventions, even before symptoms or complications appear, could be useful.

Ancestry-dependent genetic structure of the Xq28 risk haplotype in the Mexican population and its association with childhood-onset systemic lupus erythematosus

“…Notably, the frequency of the risk H1 haplotype in the MEZ population (0.47) was closer to that in the AM population (0.65) than to that in the IBS population (0.13) ( Tables 3 , 4 and Supplementary Tables 1 , 3 ). This finding is in contrast to the relationship observed for alleles harbored on autosomes, which in MEZ usually exhibit intermediate frequencies between AM and IBS ( 31 – 34 ). We also found that the variants located in TMEM187 (rs2266890 and rs13397) exhibited a significantly decreased LD r 2 value in both the MEZ and AM populations, while the LD r 2 value remained high for all analyzed SNVs in the IBS population ( Figure 1 ).…”

Functional characterization of two DYRK1B variants causative of AOMS3

“…We read with great interest the recent article entitled “Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum” by Mendoza-Caamal et al [ 1 ]. Their identification of two novel DYRK1B missense mutations (K68Q and R252H) causative of abdominal obesity metabolic syndrome-3 (AOMS3) provides a long-awaited follow-up to the original discovery of AOMS3 [ 2 ].…”

New insights into the roles for DYRK family in mammalian development and congenital diseases

“… Knockout animal Defects in knockout animal Associated diseases Ref. Lethal at E10.5 to 13.5 19 , 59 , 60 , 61 , 64 , 65 , 69 , 70 Smaller body and hypoplasia of several primitive tissues such as heart, liver, branchial arches, and brain vesicles Dosage-dependent Down syndrome Cerebral hemorrhage and defects in angiogenesis of central arteries in the developing hindbrain DYRK1A-Related Intellectual Disability Syndrome 67 , 68 Hydrocephalus with small brain size and impaired social behavior No obvious developmental defects (Detailed phenotype is not available) Abdominal obesity-metabolic syndrome 3 89 , 90 , 92 Lethal before 72 hpf 98 Shortened and curved body axis, visible loss of somites, and cyclopic eyes Loss of paraxial myoD -expression Lethal at or close to birth Skeletal ciliopathies 109 , 110 Smaller body and hypoplasia of multi organs with especially skeletal abnormality Suppression of Hedgehog signaling via abnormal ciliogenesis Dosage-independent …”

“…In humans, DYRK1B mutations are related to abdominal obesity and metabolic syndrome 3 (AOMS3), which is characterized by abdominal obesity, type 2 diabetes, hypertension, and early onset coronary artery disease. 89 , 90 Mutations H90P and R102C affect the structural element DYRK homology box and interfere with the maturation of DYRK1B by tyrosine auto-phosphorylation, thereby compromising the conformational stability of the catalytic domain and resulting in loss-of-function.…”