Transgenic mice with an R342X mutation in Phf6 display clinical features of Börjeson-Forssman-Lehmann Syndrome (BFLS).

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dc.contributor.authorAhmed, R.
dc.contributor.authorSarwar, S.
dc.contributor.authorHu, J.
dc.contributor.authorCardin, V.
dc.contributor.authorQiu, L.R.
dc.contributor.authorZapata, G.
dc.contributor.authorVandeleur, L.
dc.contributor.authorYan, K.
dc.contributor.authorLerch, J.P.
dc.contributor.authorCorbett, M.A.
dc.contributor.authorGécz, J.
dc.contributor.authorPicketts, D.J.
dc.date.issued2021
dc.description.abstractThe PHF6 mutation c.1024C>T; p.R342X, is a recurrent cause of Börjeson–Forssman–Lehmann Syndrome (BFLS), a neurodevelopmental disorder characterized by moderate–severe intellectual disability, truncal obesity, gynecomastia, hypogonadism, long tapering fingers and large ears (MIM#301900). Here, we generated transgenic mice with the identical substitution (R342X mice) using CRISPR technology.We show that the p.R342X mutation causes a reduction in PHF6 protein levels, in both human and mice, from nonsense-mediated decay and nonsense-associated alternative splicing, respectively. Magnetic resonance imaging studies indicated that R342X mice had a reduced brain volume on a mixed genetic background but developed hydrocephaly and a high incidence of postnatal death on a C57BL/6 background. Cortical development proceeded normally, while hippocampus and hypothalamus relative brain volumes were altered. A hypoplastic anterior pituitary was also observed that likely contributes to the small size of the R342X mice. Behavior testing demonstrated deficits in associative learning, spatial memory and an anxiolytic phenotype. Taken together, the R342X mice represent a good preclinical model of BFLS that will allow further dissection of PHF6 function and disease pathogenesis.
dc.description.statementofresponsibilityRaies Ahmed, Shihab Sarwar, Jinghua Hu, Valérie Cardin, Lily R. Qiu, Gerardo Zapata, Lucianne Vandeleur, Keqin Yan, Jason P. Lerch, Mark A. Corbett, Jozef Gecz, and David J. Picketts
dc.identifier.citationHuman Molecular Genetics, 2021; 30(7):575-594
dc.identifier.doi10.1093/hmg/ddab081
dc.identifier.issn0964-6906
dc.identifier.issn1460-2083
dc.identifier.orcidCorbett, M.A. [0000-0001-9298-3072]
dc.identifier.orcidGécz, J. [0000-0002-7884-6861]
dc.identifier.urihttps://hdl.handle.net/2440/145821
dc.language.isoen
dc.publisherOxford University Press (OUP)
dc.rights© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
dc.source.urihttps://doi.org/10.1093/hmg/ddab081
dc.subjectphenotype; magnetic resonance imaging; mutation; mice; transgenic; signs and symptoms
dc.subject.meshFingers
dc.subject.meshFace
dc.subject.meshBrain
dc.subject.meshCells, Cultured
dc.subject.meshAnimals
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMice, Transgenic
dc.subject.meshHumans
dc.subject.meshEpilepsy
dc.subject.meshMental Retardation, X-Linked
dc.subject.meshObesity
dc.subject.meshHypogonadism
dc.subject.meshDisease Models, Animal
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshGrowth Disorders
dc.subject.meshRepressor Proteins
dc.subject.meshMagnetic Resonance Imaging
dc.subject.meshGene Expression Profiling
dc.subject.meshAssociation Learning
dc.subject.meshMutation
dc.subject.meshFemale
dc.subject.meshMale
dc.subject.meshSpatial Memory
dc.subject.meshRNA-Seq
dc.titleTransgenic mice with an R342X mutation in Phf6 display clinical features of Börjeson-Forssman-Lehmann Syndrome (BFLS).
dc.typeJournal article
pubs.publication-statusPublished

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