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dc.contributor.authorKim, Hong Joo
dc.contributor.authorMohassel, Payam
dc.contributor.authorDonkervoort, Sandra
dc.contributor.authorGuo, Lin
dc.contributor.authorO'Donovan, Kevin
dc.contributor.authorCoughlin, Maura
dc.contributor.authorLornage, Xaviere
dc.contributor.authorFoulds, Nicola
dc.contributor.authorHammans, Simon R
dc.contributor.authorFoley, A Reghan
dc.contributor.authorFare, Charlotte M
dc.contributor.authorFord, Alice F
dc.contributor.authorOgasawara, Masashi
dc.contributor.authorSato, Aki
dc.contributor.authorIida, Aritoshi
dc.contributor.authorMunot, Pinki
dc.contributor.authorAmbegaonkar, Gautam
dc.contributor.authorPhadke, Rahul
dc.contributor.authorO'Donovan, Dominic G
dc.contributor.authorBuchert, Rebecca
dc.contributor.authorGrimmel, Mona
dc.contributor.authorTöpf, Ana
dc.contributor.authorZaharieva, Irina T
dc.contributor.authorBrady, Lauren
dc.contributor.authorHu, Ying
dc.contributor.authorLloyd, Thomas E
dc.contributor.authorKlein, Andrea
dc.contributor.authorSteinlin, Maja
dc.contributor.authorKuster, Alice
dc.contributor.authorMercier, Sandra
dc.contributor.authorMarcorelles, Pascale
dc.contributor.authorPéréon, Yann
dc.contributor.authorFleurence, Emmanuelle
dc.contributor.authorManzur, Adnan
dc.contributor.authorEnnis, Sarah
dc.contributor.authorUpstill-Goddard, Rosanna
dc.contributor.authorBello, Luca
dc.contributor.authorBertolin, Cinzia
dc.contributor.authorPegoraro, Elena
dc.contributor.authorSalviati, Leonardo
dc.contributor.authorFrench, Courtney E
dc.contributor.authorShatillo, Andriy
dc.contributor.authorRaymond, F Lucy
dc.contributor.authorHaack, Tobias B
dc.contributor.authorQuijano-Roy, Susana
dc.contributor.authorBöhm, Johann
dc.contributor.authorNelson, Isabelle
dc.contributor.authorStojkovic, Tanya
dc.contributor.authorEvangelista, Teresinha
dc.contributor.authorStraub, Volker
dc.contributor.authorRomero, Norma B
dc.contributor.authorLaporte, Jocelyn
dc.contributor.authorMuntoni, Francesco
dc.contributor.authorNishino, Ichizo
dc.contributor.authorTarnopolsky, Mark A
dc.contributor.authorShorter, James
dc.contributor.authorBönnemann, Carsten G
dc.contributor.authorTaylor, J Paul
dc.date.accessioned2022-06-07T08:09:45Z
dc.date.available2022-06-07T08:09:45Z
dc.date.issued2022-04-28
dc.identifier.issn2041-1723
dc.identifier.other35484142
dc.identifier.otherPMC9050844
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337722
dc.descriptionFunder: Howard Hughes Medical Institute
dc.description.abstractMissense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101528555
dc.sourceessn: 2041-1723
dc.subjectAnimals
dc.subjectHumans
dc.subjectMuscular Dystrophy, Oculopharyngeal
dc.subjectAmyotrophic Lateral Sclerosis
dc.subjectHeterogeneous-Nuclear Ribonucleoprotein Group A-B
dc.subjectHeterozygote
dc.subjectFrameshift Mutation
dc.titleHeterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy.
dc.typeArticle
dc.date.updated2022-06-07T08:09:44Z
prism.issueIdentifier1
prism.publicationNameNat Commun
prism.volume13
dc.identifier.doi10.17863/CAM.85131
dcterms.dateAccepted2022-03-25
rioxxterms.versionofrecord10.1038/s41467-022-30015-1
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidKim, Hong Joo [0000-0002-9157-1612]
dc.contributor.orcidMohassel, Payam [0000-0001-5313-9514]
dc.contributor.orcidFare, Charlotte M [0000-0003-0394-6435]
dc.contributor.orcidIida, Aritoshi [0000-0001-7538-1651]
dc.contributor.orcidBuchert, Rebecca [0000-0001-7576-3326]
dc.contributor.orcidLloyd, Thomas E [0000-0003-4756-3700]
dc.contributor.orcidFleurence, Emmanuelle [0000-0002-6717-3737]
dc.contributor.orcidEnnis, Sarah [0000-0003-2648-0869]
dc.contributor.orcidUpstill-Goddard, Rosanna [0000-0002-2666-0934]
dc.contributor.orcidBello, Luca [0000-0002-3075-6525]
dc.contributor.orcidSalviati, Leonardo [0000-0001-5642-9963]
dc.contributor.orcidFrench, Courtney E [0000-0001-7620-1544]
dc.contributor.orcidShatillo, Andriy [0000-0003-3630-6880]
dc.contributor.orcidRaymond, F Lucy [0000-0003-2652-3355]
dc.contributor.orcidStraub, Volker [0000-0001-9046-3540]
dc.contributor.orcidLaporte, Jocelyn [0000-0001-8256-5862]
dc.contributor.orcidNishino, Ichizo [0000-0001-9452-112X]
dc.contributor.orcidTarnopolsky, Mark A [0000-0003-0312-3746]
dc.contributor.orcidBönnemann, Carsten G [0000-0002-5930-2324]
dc.contributor.orcidTaylor, J Paul [0000-0002-5794-0349]
dc.identifier.eissn2041-1723
pubs.funder-project-idU.S. Department of Health &amp (R35NS097974)
pubs.funder-project-idU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (R35NS097974)
pubs.funder-project-idTelethon (GTB12001D)
cam.issuedOnline2022-04-28


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International