B-Po05-025 Using Exome Sequencing to Uncover a Popdc2 Variant as a Novel Candidate Cause of Familial Junctional Ectopic Tachycardia

Helm, Benjamin M.; Swan, Alexander H.; Brand, Thomas; Steinberg, Leonard A.; Kean, Adam C.

doi:10.1016/j.hrthm.2021.06.945

Cited by 2 publications

(4 citation statements)

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“…BVES and POPDC3 mutations display recessive inheritance, while POPDC2 mutations show a dominant mode [ 5 , 10 , 11 , 15 , 17 , 19 , 37 , 40 , 50 , 53 , 57 ]. If disruption of stoichiometric POPDC1–POPDC2 complexes played an equal role in the mechanism of mutations of both of isoforms, identical modes of inheritance would be expected.…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned, POPDC isoforms are differentially expressed across tissues, and this is also reflected in the observed phenotypes of patients expressing variants of these proteins. Patients carrying POPDC2 variants show only cardiac arrhythmias [ 17 , 37 ], while POPDC3 variants are only associated with LGMD [ 50 , 53 , 57 ]. In contrast, patients carrying BVES variants develop cardiac and/or skeletal muscle phenotypes [ 5 , 10 , 11 , 15 , 19 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

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

Swan

Schindler

Savarese

et al. 2023

acta neuropathol commun

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Swan

Schindler

Savarese

et al. 2023

acta neuropathol commun

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“…Patients carrying mutations in POPDC1 develop a recessive form of limb-girdle muscular dystrophy (LGMDR25) with highly variable onset and in addition displaying sinus bradycardia and an AV-block of varying severity [29,[134][135][136][137]. Mutations found in POPDC2 cause patients to develop a cardiac arrhythmia phenotype but importantly do not display any skeletal muscle phenotype [138,139]. In contrast, patients carrying mutations in POPDC3 display a severe limb-girdle muscular dystrophy (LGMDR26) but a normal heart [140].…”

Section: Mutations In Popdc Genes Are Causing Heart and Muscle Diseasementioning

confidence: 99%

“…A novel missense POPDC2 L245P mutation has been recently reported in a family of four that developed congenital junctional ectopic tachycardia (cJET) [139]. cJET is an extremely rare tachyarrhythmia which develops in infants, and previously, only a single gene, TNNI3K, has been linked to familial cJET cases [145].…”

Section: Mutations In Popdc Genes Are Causing Heart and Muscle Diseasementioning

confidence: 99%

The Role of POPDC Proteins in Cardiac Pacemaking and Conduction

Gruscheski

Brand

2021

JCDD

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The Popeye domain-containing (POPDC) gene family, consisting of Popdc1 (also known as Bves), Popdc2, and Popdc3, encodes transmembrane proteins abundantly expressed in striated muscle. POPDC proteins have recently been identified as cAMP effector proteins and have been proposed to be part of the protein network involved in cAMP signaling. However, their exact biochemical activity is presently poorly understood. Loss-of-function mutations in animal models causes abnormalities in skeletal muscle regeneration, conduction, and heart rate adaptation after stress. Likewise, patients carrying missense or nonsense mutations in POPDC genes have been associated with cardiac arrhythmias and limb-girdle muscular dystrophy. In this review, we introduce the POPDC protein family, and describe their structure function, and role in cAMP signaling. Furthermore, the pathological phenotypes observed in zebrafish and mouse models and the clinical and molecular pathologies in patients carrying POPDC mutations are described.

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B-Po05-025 Using Exome Sequencing to Uncover a Popdc2 Variant as a Novel Candidate Cause of Familial Junctional Ectopic Tachycardia

Cited by 2 publications

References 0 publications

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

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

The Role of POPDC Proteins in Cardiac Pacemaking and Conduction

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