DYRK1B – Abdominal obesity–Metabolic syndrome 3

Abdominal obesity–metabolic syndrome 3 (AOMS3; MONDO:0014352) is a rare autosomal-dominant disorder characterized by early-onset truncal obesity, insulin resistance, labile type 2 diabetes, hypertriglyceridemia, and hypertension. DYRK1B (HGNC:3092) encodes a dual-specificity tyrosine-phosphorylation-regulated kinase implicated in adipogenesis and gluconeogenesis.

In three large families, the DH-box variants c.269A>C (p.His90Pro) and c.304C>T (p.Arg102Cys) co-segregated with the full AOMS3 phenotype in all affected members (PMID:24827035). In two additional pedigrees, the variants c.202A>C (p.Lys68Gln) and c.755G>A (p.Arg252His) were each found in a single proband and fully co-segregated with AOMS3 across multiple generations (PMID:34193236). All variants display autosomal-dominant inheritance with complete penetrance.

The variant spectrum includes four missense substitutions clustering in the DH-box or kinase domain, each shown to impair DYRK1B functionality in silico or by co-segregation. Recurrent founder alleles R102C and H90P were identified in ethnically distinct families, whereas the K68Q and R252H variants were novel findings in two Latin American kindreds.

Functional assays demonstrate that R102C and H90P disrupt tyrosine autophosphorylation and promote detergent-insoluble aggregation, consistent with altered chaperone-dependent maturation (PMID:28743892). Gain-of-function studies revealed potentiated inhibition of SHH and Wnt pathways and enhanced adipogenesis and glucose-6-phosphatase expression in R102C (PMID:24827035). More recent analyses of K68Q and R252H variants confirmed intact catalytic activity but aberrant nuclear translocation, underscoring non-enzymatic mechanisms of pathogenicity (PMID:38867326).

No conflicting reports have disputed the dominant association of DYRK1B variants with AOMS3. Mouse and cellular studies of DYRK1B splicing variants further support a critical role in adipocyte differentiation and metabolic homeostasis, although these exceed current scoring criteria.

Together, robust segregation in five pedigrees and concordant functional alterations substantiate a Strong gene–disease relationship for DYRK1B–AOMS3. Genetic testing for DYRK1B variants is clinically actionable for early diagnosis and management of monogenic metabolic syndrome.

References

• Orphanet Journal of Rare Diseases • 2021 • Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum. PMID:34193236
• The New England Journal of Medicine • 2014 • A form of the metabolic syndrome associated with mutations in DYRK1B. PMID:24827035
• Scientific Reports • 2017 • DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain. PMID:28743892
• Orphanet Journal of Rare Diseases • 2024 • Functional characterization of two DYRK1B variants causative of AOMS3. PMID:38867326

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