TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis

Hum Mutat. 2019 Oct;40(10):1886-1898. doi: 10.1002/humu.23834. Epub 2019 Jun 27.


Transforming growth factor β-activated kinase 1 (TAK1) mediates multiple biological processes through the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathways. TAK1 activation is tightly regulated by its binding partners (TABs). In particular, binding with TAB2 is crucial for cardiovascular development and extracellular matrix (ECM) homeostasis. In our previous work, we reported a novel multisystem disorder associated with the heterozygous TAB2 c.1398dup variant. Here, we dissect the functional effects of this variant in order to understand its molecular pathogenesis. We demonstrate that TAB2 c.1398dup considerably undergoes to nonsense-mediated messenger RNA decay and encodes a truncated protein that loses its ability to bind TAK1. We also show an alteration of the TAK1 autophosphorylation status and of selected downstream signaling pathways in patients' fibroblasts. Immunofluorescence analyses and ECM-related polymerase chain reaction-array panels highlight that patient fibroblasts display ECM disorganization and altered expression of selected ECM components and collagen-related pathways. In conclusion, we deeply dissect the molecular pathogenesis of the TAB2 c.1398dup variant and show that the resulting phenotype is well explained by TAB2 loss-of-function. Our data also offer initial insights on the ECM homeostasis impairment as a molecular mechanism probably underlying a multisystem disorder linked to TAB2.

Keywords: MAPK signaling pathways; TAK1-TAB complex; collagen; extracellular matrix; haploinsufficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Cell Line
  • Cell Proliferation
  • DNA Mutational Analysis
  • Extracellular Matrix / metabolism*
  • Fibroblasts / metabolism
  • Genetic Variation*
  • Haploinsufficiency*
  • Homeostasis*
  • Humans
  • MAP Kinase Kinase Kinases / metabolism
  • Mutation
  • Nonsense Mediated mRNA Decay
  • Phosphorylation
  • Protein Binding
  • Signal Transduction


  • Adaptor Proteins, Signal Transducing
  • TAB2 protein, human
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7