The Popeye domain containing 2 (popdc2) gene in zebrafish is required for heart and skeletal muscle development

Kirchmaier, Bettina C.; Poon, Kar Lai; Schwerte, Thorsten; Huisken, Jan; Winkler, Christoph; Jungblut, Benno; Stainier, Didier Y. R.; Brand, Thomas

doi:10.1016/j.ydbio.2012.01.015

Cited by 60 publications

(104 citation statements)

References 61 publications

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“…It can be envisioned that the lack of proper matrix assembly provides insufficient mechanical linkage, leading to fiber detachment when the zebrafish larvae start to swim. Identical phenotypes were observed for popdc1 (this study and Supplemental Figure 14) and popdc2 morphants (15), suggesting that both genes are probably acting together in the same pathway. Presently, it is unclear how POPDC proteins are linked to MTJ formation and ECM accumulation and what role cAMP signaling might have in these processes; however, the fact that POPDC1 interacts with DYS (and DYSF and CAV-3) suggests that it might be involved in laminin-DAG linkage formation (37,38).…”

Section: Discussionsupporting

confidence: 71%

“…Some morphants (20%) displayed a 2:1 AV block, a phenotype that has been previously reported for popdc2 morphants (Supplemental Figure 15G, Supplemental Videos 1 and 2, and ref. 15). Upon closer inspection, skeletal muscle was also affected in 80% of the morphants and was characterized by myofibrillar misalignment and fiber detachment (Supplemental Figure 15H).…”

Section: Discussionmentioning

confidence: 99%

“…Both Popdc1 and Popdc2 null mutants display a stress-induced sinus node bradycardia, which develops in an age-dependent manner (10,14). In zebrafish, popdc2 morphants develop embryonic heart failure, atrioventricular (AV) block, and muscular dystrophy (15). Thus, both heart and skeletal muscle pathologies have been associated in model organisms with the loss of either Popdc1 or Popdc2.…”

Section: Popdc1 S201fmentioning

confidence: 99%

“…Whole-mount in situ hybridization was carried out as described previously (15). A partial clone of popdc1 cDNA was subcloned into the pGEMTeasy vector (Promega).…”

Section: Wesmentioning

confidence: 99%

“…Whole-mount immunostaining was performed as described previously (15). The following primary antibodies were used: monoclonal F59 (DHSB), monoclonal F310 (DHSB), monoclonal antisarcomeric α-actinin (A7811, Sigma-Aldrich), anti-DYS (D8043, Sigma-Aldrich), and anti-vinculin (FAK100, Millipore).…”

Section: Wesmentioning

confidence: 99%

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POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

Schindler

Scotton

Zhang

et al. 2015

Journal of Clinical Investigation

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292

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The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1S201F displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1S201F and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1S201F in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1S191F) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Popdc1 S201fmentioning

confidence: 99%

“…Whole-mount in situ hybridization was carried out as described previously (15). A partial clone of popdc1 cDNA was subcloned into the pGEMTeasy vector (Promega).…”

Section: Wesmentioning

confidence: 99%

Section: Wesmentioning

confidence: 99%

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POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

Schindler

Scotton

Zhang

et al. 2015

Journal of Clinical Investigation

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292

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POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

Vissing

Johnson

Töpf

et al. 2019

Annals of Neurology

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Objective The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene. Methods We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK‐1 current. Results We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy‐terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands’ muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice‐site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano‐gated potassium channel, TREK‐1. Interpretation Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832–843

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Homozygous missense variant in POPDC3 causes recessive limb‐girdle muscular dystrophy type 26

Ullah

Lin

Younus

et al. 2022

The Journal of Gene Medicine

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Background: Limb-girdle muscular dystrophy (LGMD) comprises a heterogeneous group of diseases, affecting different muscles, predominantly skeletal muscles and cardiac muscles of the body. LGMD is classified into two main subtypes A and B, which are further subclassified into eight dominant and thirty recessive subtypes.Three genes, namely POPDC1, POPDC2 and POPDC3, encode popeye domaincontaining protein (POPDC), and the variants of POPDC1 and POPDC3 genes have been associated with LGMD.Methods: In the present study, we performed whole-exome sequencing (WES) analysis on a single-family to investigate the hallmark features of LGMD. The results of WES were further confirmed by Sanger sequencing and 3D protein modeling was also conducted.Results: WES data analysis and Sanger sequencing revealed a homozygous missense variant (c.460A>G; p.Lys154Glu) at a highly conserved amino acid position in the POPDC3. Mutations in the POPDC3 gene have been previously associated with recessive limb-girdle muscular dystrophy type 26. 3D protein modeling further suggested that the identified variant might affect the POPDC3 structure and proper function.

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The Popeye domain containing 2 (popdc2) gene in zebrafish is required for heart and skeletal muscle development

Cited by 60 publications

References 61 publications

POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

Homozygous missense variant in POPDC3 causes recessive limb‐girdle muscular dystrophy type 26

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