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

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...

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Published in:Annals of neurology 2019-12, Vol.86 (6), p.832-843
Main Authors: Vissing, John, Johnson, Katherine, Töpf, Ana, Nafissi, Shahriar, Díaz‐Manera, Jordi, French, Vanessa M., Schindler, Roland F., Sarathchandra, Padmini, Løkken, Nicoline, Rinné, Susanne, Freund, Max, Decher, Niels, Müller, Thomas, Duno, Morten, Krag, Thomas, Brand, Thomas, Straub, Volker
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cited_by cdi_FETCH-LOGICAL-c3880-1f8334ee2f55162ef2ed880172f7f414739a392c168875d0311acd63ab349ad23
cites cdi_FETCH-LOGICAL-c3880-1f8334ee2f55162ef2ed880172f7f414739a392c168875d0311acd63ab349ad23
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container_issue 6
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container_title Annals of neurology
container_volume 86
creator Vissing, John
Johnson, Katherine
Töpf, Ana
Nafissi, Shahriar
Díaz‐Manera, Jordi
French, Vanessa M.
Schindler, Roland F.
Sarathchandra, Padmini
Løkken, Nicoline
Rinné, Susanne
Freund, Max
Decher, Niels
Müller, Thomas
Duno, Morten
Krag, Thomas
Brand, Thomas
Straub, Volker
description 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
doi_str_mv 10.1002/ana.25620
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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</description><identifier>ISSN: 0364-5134</identifier><identifier>EISSN: 1531-8249</identifier><identifier>DOI: 10.1002/ana.25620</identifier><identifier>PMID: 31610034</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley &amp; Sons, Inc</publisher><subject>Adenosine monophosphate ; Adult ; Animals ; Biopsy ; Cell Adhesion Molecules - chemistry ; Cell Adhesion Molecules - genetics ; Cohort Studies ; Creatine ; Creatine kinase ; Cyclic AMP ; Danio rerio ; Domains ; Dystrophy ; Female ; Gametocytes ; Gastric cancer ; Gene Knockdown Techniques - methods ; Genetic Variation - genetics ; Humans ; Kinases ; Larvae ; Magnetic resonance imaging ; Male ; Membrane proteins ; Middle Aged ; Muscle Proteins - chemistry ; Muscle Proteins - genetics ; Muscle, Skeletal - diagnostic imaging ; Muscle, Skeletal - physiology ; Muscles ; Muscular Dystrophies, Limb-Girdle - diagnostic imaging ; Muscular Dystrophies, Limb-Girdle - genetics ; Muscular dystrophy ; Mutants ; NMR ; Nuclear magnetic resonance ; Oocytes ; Pedigree ; Potassium ; Protein Structure, Secondary ; Proteins ; Serum levels ; Skeletal muscle ; Xenopus laevis ; Zebrafish</subject><ispartof>Annals of neurology, 2019-12, Vol.86 (6), p.832-843</ispartof><rights>2019 American Neurological Association</rights><rights>2019 American Neurological Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3880-1f8334ee2f55162ef2ed880172f7f414739a392c168875d0311acd63ab349ad23</citedby><cites>FETCH-LOGICAL-c3880-1f8334ee2f55162ef2ed880172f7f414739a392c168875d0311acd63ab349ad23</cites><orcidid>0000-0001-6144-8544 ; 0000-0003-2941-7988</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31610034$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vissing, John</creatorcontrib><creatorcontrib>Johnson, Katherine</creatorcontrib><creatorcontrib>Töpf, Ana</creatorcontrib><creatorcontrib>Nafissi, Shahriar</creatorcontrib><creatorcontrib>Díaz‐Manera, Jordi</creatorcontrib><creatorcontrib>French, Vanessa M.</creatorcontrib><creatorcontrib>Schindler, Roland F.</creatorcontrib><creatorcontrib>Sarathchandra, Padmini</creatorcontrib><creatorcontrib>Løkken, Nicoline</creatorcontrib><creatorcontrib>Rinné, Susanne</creatorcontrib><creatorcontrib>Freund, Max</creatorcontrib><creatorcontrib>Decher, Niels</creatorcontrib><creatorcontrib>Müller, Thomas</creatorcontrib><creatorcontrib>Duno, Morten</creatorcontrib><creatorcontrib>Krag, Thomas</creatorcontrib><creatorcontrib>Brand, Thomas</creatorcontrib><creatorcontrib>Straub, Volker</creatorcontrib><title>POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy</title><title>Annals of neurology</title><addtitle>Ann Neurol</addtitle><description>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</description><subject>Adenosine monophosphate</subject><subject>Adult</subject><subject>Animals</subject><subject>Biopsy</subject><subject>Cell Adhesion Molecules - chemistry</subject><subject>Cell Adhesion Molecules - genetics</subject><subject>Cohort Studies</subject><subject>Creatine</subject><subject>Creatine kinase</subject><subject>Cyclic AMP</subject><subject>Danio rerio</subject><subject>Domains</subject><subject>Dystrophy</subject><subject>Female</subject><subject>Gametocytes</subject><subject>Gastric cancer</subject><subject>Gene Knockdown Techniques - methods</subject><subject>Genetic Variation - genetics</subject><subject>Humans</subject><subject>Kinases</subject><subject>Larvae</subject><subject>Magnetic resonance imaging</subject><subject>Male</subject><subject>Membrane proteins</subject><subject>Middle Aged</subject><subject>Muscle Proteins - chemistry</subject><subject>Muscle Proteins - genetics</subject><subject>Muscle, Skeletal - diagnostic imaging</subject><subject>Muscle, Skeletal - physiology</subject><subject>Muscles</subject><subject>Muscular Dystrophies, Limb-Girdle - diagnostic imaging</subject><subject>Muscular Dystrophies, Limb-Girdle - genetics</subject><subject>Muscular dystrophy</subject><subject>Mutants</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Oocytes</subject><subject>Pedigree</subject><subject>Potassium</subject><subject>Protein Structure, Secondary</subject><subject>Proteins</subject><subject>Serum levels</subject><subject>Skeletal muscle</subject><subject>Xenopus laevis</subject><subject>Zebrafish</subject><issn>0364-5134</issn><issn>1531-8249</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp10EtLw0AUBeBBFFurC_-ADLjRRdq5czN5LENrq1DbLtRtmCYTGsmjziSU_HtHU10Irg5cPg6XQ8g1sDEwxieykmMuPM5OyBAEghNwNzwlQ4ae6whAd0AujHlnjIUesHMyQLDJ0B2SzWa9mU2RLlSl6JvUuawaQyNj6iSXjaKHvNlRSVfqQOe1Lmmd0WVebuki12mh6HNrkraQms460-h6v-suyVkmC6Oujjkir_OHl-mjs1wvnqbR0kkwCJgDWYDoKsUzIcDjKuMqtXfweeZnLrg-hhJDnoAXBL5IGQLIJPVQbtENZcpxRO763r2uP1plmrjMTaKKQlaqbk3MkYmAcQ5o6e0f-l63urLfWQVC-AK90Kr7XiW6NkarLN7rvJS6i4HFXzPHdub4e2Zrb46N7bZU6a_82dWCSQ8OeaG6_5viaBX1lZ_XloKQ</recordid><startdate>201912</startdate><enddate>201912</enddate><creator>Vissing, John</creator><creator>Johnson, Katherine</creator><creator>Töpf, Ana</creator><creator>Nafissi, Shahriar</creator><creator>Díaz‐Manera, Jordi</creator><creator>French, Vanessa M.</creator><creator>Schindler, Roland F.</creator><creator>Sarathchandra, Padmini</creator><creator>Løkken, Nicoline</creator><creator>Rinné, Susanne</creator><creator>Freund, Max</creator><creator>Decher, Niels</creator><creator>Müller, Thomas</creator><creator>Duno, Morten</creator><creator>Krag, Thomas</creator><creator>Brand, Thomas</creator><creator>Straub, Volker</creator><general>John Wiley &amp; Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6144-8544</orcidid><orcidid>https://orcid.org/0000-0003-2941-7988</orcidid></search><sort><creationdate>201912</creationdate><title>POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy</title><author>Vissing, John ; Johnson, Katherine ; Töpf, Ana ; Nafissi, Shahriar ; Díaz‐Manera, Jordi ; French, Vanessa M. ; Schindler, Roland F. ; Sarathchandra, Padmini ; Løkken, Nicoline ; Rinné, Susanne ; Freund, Max ; Decher, Niels ; Müller, Thomas ; Duno, Morten ; Krag, Thomas ; Brand, Thomas ; Straub, Volker</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3880-1f8334ee2f55162ef2ed880172f7f414739a392c168875d0311acd63ab349ad23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adenosine monophosphate</topic><topic>Adult</topic><topic>Animals</topic><topic>Biopsy</topic><topic>Cell Adhesion Molecules - chemistry</topic><topic>Cell Adhesion Molecules - genetics</topic><topic>Cohort Studies</topic><topic>Creatine</topic><topic>Creatine kinase</topic><topic>Cyclic AMP</topic><topic>Danio rerio</topic><topic>Domains</topic><topic>Dystrophy</topic><topic>Female</topic><topic>Gametocytes</topic><topic>Gastric cancer</topic><topic>Gene Knockdown Techniques - methods</topic><topic>Genetic Variation - genetics</topic><topic>Humans</topic><topic>Kinases</topic><topic>Larvae</topic><topic>Magnetic resonance imaging</topic><topic>Male</topic><topic>Membrane proteins</topic><topic>Middle Aged</topic><topic>Muscle Proteins - chemistry</topic><topic>Muscle Proteins - genetics</topic><topic>Muscle, Skeletal - diagnostic imaging</topic><topic>Muscle, Skeletal - physiology</topic><topic>Muscles</topic><topic>Muscular Dystrophies, Limb-Girdle - diagnostic imaging</topic><topic>Muscular Dystrophies, Limb-Girdle - genetics</topic><topic>Muscular dystrophy</topic><topic>Mutants</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Oocytes</topic><topic>Pedigree</topic><topic>Potassium</topic><topic>Protein Structure, Secondary</topic><topic>Proteins</topic><topic>Serum levels</topic><topic>Skeletal muscle</topic><topic>Xenopus laevis</topic><topic>Zebrafish</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vissing, John</creatorcontrib><creatorcontrib>Johnson, Katherine</creatorcontrib><creatorcontrib>Töpf, Ana</creatorcontrib><creatorcontrib>Nafissi, Shahriar</creatorcontrib><creatorcontrib>Díaz‐Manera, Jordi</creatorcontrib><creatorcontrib>French, Vanessa M.</creatorcontrib><creatorcontrib>Schindler, Roland F.</creatorcontrib><creatorcontrib>Sarathchandra, Padmini</creatorcontrib><creatorcontrib>Løkken, Nicoline</creatorcontrib><creatorcontrib>Rinné, Susanne</creatorcontrib><creatorcontrib>Freund, Max</creatorcontrib><creatorcontrib>Decher, Niels</creatorcontrib><creatorcontrib>Müller, Thomas</creatorcontrib><creatorcontrib>Duno, Morten</creatorcontrib><creatorcontrib>Krag, Thomas</creatorcontrib><creatorcontrib>Brand, Thomas</creatorcontrib><creatorcontrib>Straub, Volker</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Annals of neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vissing, John</au><au>Johnson, Katherine</au><au>Töpf, Ana</au><au>Nafissi, Shahriar</au><au>Díaz‐Manera, Jordi</au><au>French, Vanessa M.</au><au>Schindler, Roland F.</au><au>Sarathchandra, Padmini</au><au>Løkken, Nicoline</au><au>Rinné, Susanne</au><au>Freund, Max</au><au>Decher, Niels</au><au>Müller, Thomas</au><au>Duno, Morten</au><au>Krag, Thomas</au><au>Brand, Thomas</au><au>Straub, Volker</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy</atitle><jtitle>Annals of neurology</jtitle><addtitle>Ann Neurol</addtitle><date>2019-12</date><risdate>2019</risdate><volume>86</volume><issue>6</issue><spage>832</spage><epage>843</epage><pages>832-843</pages><issn>0364-5134</issn><eissn>1531-8249</eissn><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. 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subjects Adenosine monophosphate
Adult
Animals
Biopsy
Cell Adhesion Molecules - chemistry
Cell Adhesion Molecules - genetics
Cohort Studies
Creatine
Creatine kinase
Cyclic AMP
Danio rerio
Domains
Dystrophy
Female
Gametocytes
Gastric cancer
Gene Knockdown Techniques - methods
Genetic Variation - genetics
Humans
Kinases
Larvae
Magnetic resonance imaging
Male
Membrane proteins
Middle Aged
Muscle Proteins - chemistry
Muscle Proteins - genetics
Muscle, Skeletal - diagnostic imaging
Muscle, Skeletal - physiology
Muscles
Muscular Dystrophies, Limb-Girdle - diagnostic imaging
Muscular Dystrophies, Limb-Girdle - genetics
Muscular dystrophy
Mutants
NMR
Nuclear magnetic resonance
Oocytes
Pedigree
Potassium
Protein Structure, Secondary
Proteins
Serum levels
Skeletal muscle
Xenopus laevis
Zebrafish
title POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy
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