%0 Journal Article %1 vissing2019popdc3 %A Vissing, J. %A Johnson, K. %A Topf, A. %A Nafissi, S. %A Diaz-Manera, J. %A French, V. M. %A Schindler, R. F. %A Sarathchandra, P. %A Lokken, N. %A Rinne, S. %A Freund, M. %A Decher, N. %A Muller, T. %A Duno, M. %A Krag, T. %A Brand, T. %A Straub, V. %D 2019 %J Ann Neurol %K Adult myOwn %N 6 %P 832-843 %R 10.1002/ana.25620 %T POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy %U https://www.ncbi.nlm.nih.gov/pubmed/31610034 %V 86 %X 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.

@article{vissing2019popdc3, abstract = {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.}, added-at = {2024-02-15T15:08:22.000+0100}, author = {Vissing, J. and Johnson, K. and Topf, A. and Nafissi, S. and Diaz-Manera, J. and French, V. M. and Schindler, R. F. and Sarathchandra, P. and Lokken, N. and Rinne, S. and Freund, M. and Decher, N. and Muller, T. and Duno, M. and Krag, T. and Brand, T. and Straub, V.}, biburl = {https://www.bibsonomy.org/bibtex/245d2fd691ed7a33f5285ef6daa2e9a0a/jvsi_all}, doi = {10.1002/ana.25620}, interhash = {3765ead65245d253eaef58d70fc76ba0}, intrahash = {45d2fd691ed7a33f5285ef6daa2e9a0a}, issn = {1531-8249 (Electronic) 0364-5134 (Linking)}, journal = {Ann Neurol}, keywords = {Adult myOwn}, note = {Vissing, John Johnson, Katherine Topf, Ana Nafissi, Shahriar Diaz-Manera, Jordi French, Vanessa M Schindler, Roland F Sarathchandra, Padmini Lokken, Nicoline Rinne, Susanne Freund, Max Decher, Niels Muller, Thomas Duno, Morten Krag, Thomas Brand, Thomas Straub, Volker eng Ultragenyx Pharmaceuticals/International Sanofi Genzyme/International Samantha J. Brazzo Foundation/International LGMD2D Foundation/International Kurt+Peter Foundation/International PG/14/46/30911/BHF_/British Heart Foundation/United Kingdom LGMD2I Research Fund/International Magdi Yacoub Institute/International Muscular Dystrophy UK/International Coalition to Cure Calpain 3/International University Medical Center Giessen and Marburg/International PG/14/83/31128/BHF_/British Heart Foundation/United Kingdom Research Support, Non-U.S. Gov't 2019/10/15 Ann Neurol. 2019 Dec;86(6):832-843. doi: 10.1002/ana.25620. Epub 2019 Oct 28.}, number = 6, pages = {832-843}, timestamp = {2024-02-15T15:08:22.000+0100}, title = {POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy}, type = {Journal Article}, url = {https://www.ncbi.nlm.nih.gov/pubmed/31610034}, volume = 86, year = 2019 }