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• W4306658409 abstract "Abstract Background The Popeye domain containing (POPDC) genes encode sarcolemma-localised cAMP effector proteins. Mutations in BVES (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. Methods 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 interaction. Findings 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. This is in contrast to variants such as BVES p.Q153X or POPDC2 p.W188X, which 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. Interpretation Mutations in POPDC proteins that cause an impairment in membrane localisation affect POPDC complex formation while mutations which leave the protein interaction intact likely affect some other essential function of POPDC proteins. Funding This study was funded by an EPSRC/British Heart Foundation co-funded Imperial Institute of Chemical Biology (ICB) Centre for Doctoral Training (CDT) PhD studentship (EP/S023518/1), a project grant of the British Heart Foundation (PG19/13/34247) and the Deutsche Forschungsgemeinschaft (DE1482/9-1). Research in Context Evidence before this study Several biallelic missense and nonsense variants in BVES (POPDC1) have been described and are associated with heart and skeletal muscle disease. Skeletal muscle biopsies of homozygous carriers of these variants display a loss of sarcolemmal localisation of POPDC1 and POPDC2. Added value of this study We demonstrate that POPDC1 and POPDC2 form a heteromeric complex and that complex formation is required for plasma membrane trafficking of POPDC proteins. Transfection of different disease variants in HEK293 cells replicates their defective membrane targeting observed in biopsy material. Structural modelling and site-directed mutagenesis identifies an interface of strongly conserved hydrophobic residues in POPDC proteins, which likely mediate the interaction of POPDC proteins. Implications of all the available evidence These data provide novel insight into the membrane targeting requirements of POPDC proteins. We recommend testing the membrane targeting properties of any novel variant in POPDC isoforms using a newly developed co-transfection assay in HEK293 cells to characterise its pathogenicity. Our novel insight into the requirement of heterodimerization for proper membrane targeting may also offer novel opportunities to treat patients carrying mutations in POPDC proteins." @default.
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• W4306658409 date "2022-10-17" @default.
• W4306658409 modified "2023-10-16" @default.
• W4306658409 title "Differential Effects of Mutations of Popeye Domain Containing Proteins on Heteromeric Interaction and Membrane Trafficking" @default.
• W4306658409 cites W1571586310 @default.
• W4306658409 cites W1654156243 @default.
• W4306658409 cites W1803102843 @default.
• W4306658409 cites W1970607639 @default.
• W4306658409 cites W1974772536 @default.
• W4306658409 cites W1975204805 @default.
• W4306658409 cites W1978365857 @default.
• W4306658409 cites W1991240772 @default.
• W4306658409 cites W1995453746 @default.
• W4306658409 cites W2001225296 @default.
• W4306658409 cites W2004468088 @default.
• W4306658409 cites W2004781384 @default.
• W4306658409 cites W2009603488 @default.
• W4306658409 cites W2012439821 @default.
• W4306658409 cites W2021988272 @default.
• W4306658409 cites W2023963126 @default.
• W4306658409 cites W2028717691 @default.
• W4306658409 cites W2029416847 @default.
• W4306658409 cites W2044825415 @default.
• W4306658409 cites W2061684132 @default.
• W4306658409 cites W2077669553 @default.
• W4306658409 cites W2084240593 @default.
• W4306658409 cites W2087072817 @default.
• W4306658409 cites W2090649877 @default.
• W4306658409 cites W2110469184 @default.
• W4306658409 cites W2129305902 @default.
• W4306658409 cites W2153373178 @default.
• W4306658409 cites W2156964989 @default.
• W4306658409 cites W2158337573 @default.
• W4306658409 cites W2160210116 @default.
• W4306658409 cites W2166663852 @default.
• W4306658409 cites W2167279371 @default.
• W4306658409 cites W2174490601 @default.
• W4306658409 cites W2193044843 @default.
• W4306658409 cites W2399229449 @default.
• W4306658409 cites W2755115454 @default.
• W4306658409 cites W2794265066 @default.
• W4306658409 cites W2931340916 @default.
• W4306658409 cites W2936956377 @default.
• W4306658409 cites W2952178291 @default.
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• W4306658409 cites W3106630785 @default.
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• W4306658409 cites W3183475563 @default.
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• W4306658409 cites W4226048348 @default.
• W4306658409 cites W4226350133 @default.
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• W4306658409 doi "https://doi.org/10.1101/2022.10.13.511879" @default.
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