Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking

Alexander H. Swan, Roland F.R. Schindler, Marco Savarese, Isabelle Mayer, Susanne Rinné, Felix Bleser, Anne Schänzer, Andreas Hahn, Mario Sabatelli, Francesco Perna, Kathryn Chapman, Mark Pfuhl, Alan C. Spivey, Niels Decher, Bjarne Udd, Giorgio Tasca, Thomas Brand*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


The Popeye domain containing (POPDC) genes encode sarcolemma-localized cAMP effector proteins. Mutations in blood vessel epicardial substance (BVES) also known as POPDC1 and POPDC2 have been associated with limb-girdle muscular dystrophy and cardiac arrhythmia. Muscle biopsies of affected patients display impaired membrane trafficking of both POPDC isoforms. Biopsy material of patients carrying mutations in BVES were immunostained with POPDC antibodies. The interaction of POPDC proteins was investigated by co-precipitation, proximity ligation, bioluminescence resonance energy transfer and bimolecular fluorescence complementation. Site-directed mutagenesis was utilised to map the domains involved in protein–protein interaction. Patients carrying a novel homozygous variant, BVES (c.547G > T, p.V183F) displayed only a skeletal muscle pathology and a mild impairment of membrane trafficking of both POPDC isoforms. In contrast, variants such as BVES p.Q153X or POPDC2 p.W188X were associated with a greater impairment of membrane trafficking. Co-transfection analysis in HEK293 cells revealed that POPDC proteins interact with each other through a helix-helix interface located at the C-terminus of the Popeye domain. Site-directed mutagenesis of an array of ultra-conserved hydrophobic residues demonstrated that some of them are required for membrane trafficking of the POPDC1–POPDC2 complex. Mutations in POPDC proteins that cause an impairment in membrane localization affect POPDC complex formation while mutations which leave protein–protein interaction intact likely affect some other essential function of POPDC proteins.

Original languageEnglish
Article number4
JournalActa Neuropathologica Communications
Issue number1
Publication statusPublished - Dec 2023


  • Cyclic nucleotide binding domain
  • Limb-girdle muscular dystrophy
  • Membrane trafficking
  • Mutation
  • Popeye domain
  • Protein–protein interaction
  • α-helix


Dive into the research topics of 'Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking'. Together they form a unique fingerprint.

Cite this