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dc.contributor.authorRehman, Atteeq U
dc.contributor.authorNajafi, Maryam
dc.contributor.authorKambouris, Marios
dc.contributor.authorAl-Gazali, Lihadh
dc.contributor.authorMakrythanasis, Periklis
dc.contributor.authorRad, Abolfazl
dc.contributor.authorMaroofian, Reza
dc.contributor.authorRajab, Anna
dc.contributor.authorStark, Zornitza
dc.contributor.authorHunter, Jill V
dc.contributor.authorBakey, Zeineb
dc.contributor.authorTokita, Mari J
dc.contributor.authorHe, Weimin
dc.contributor.authorRichmond, Christopher
dc.contributor.authoret al.
dc.date.accessioned2020-12-11T06:27:03Z
dc.date.available2020-12-11T06:27:03Z
dc.date.issued2019
dc.identifier.issn1059-7794
dc.identifier.doi10.1002/humu.23694
dc.identifier.urihttp://hdl.handle.net/10072/400196
dc.description.abstractHuman Mutation published by Wiley Periodicals, Inc. Next-generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co-immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin-488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherWILEY
dc.relation.ispartofpagefrom267
dc.relation.ispartofpageto280
dc.relation.ispartofissue3
dc.relation.ispartofjournalHuman Mutation
dc.relation.ispartofvolume40
dc.subject.fieldofresearchGenetics
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchcode3105
dc.subject.fieldofresearchcode3202
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsGenetics & Heredity
dc.subject.keywordsearly endosome
dc.subject.keywordsendo-lysosome
dc.titleBiallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationRehman, AU; Najafi, M; Kambouris, M; Al-Gazali, L; Makrythanasis, P; Rad, A; Maroofian, R; Rajab, A; Stark, Z; Hunter, JV; Bakey, Z; Tokita, MJ; He, W; Richmond, C; et al., Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function, Human Mutation, 2019, 40 (3), pp. 267-280
dcterms.dateAccepted2018-11-22
dcterms.licensehttps://creativecommons.org/licenses/by-nc/4.0/
dc.date.updated2020-12-11T06:22:42Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2018 The Authors. HumanMutation published byWiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
gro.hasfulltextFull Text
gro.griffith.authorRichmond, Chris M.


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