Show simple item record

dc.contributor.authorCuvertino, S
dc.contributor.authorStuart, HM
dc.contributor.authorChandler, KE
dc.contributor.authorRoberts, NA
dc.contributor.authorArmstrong, R
dc.contributor.authorBernardini, L
dc.contributor.authorBhaskar, S
dc.contributor.authorCallewaert, B
dc.contributor.authorClayton-Smith, J
dc.contributor.authorHernando Davalillo, C
dc.contributor.authorDeshpande, C
dc.contributor.authorDevriendt, K
dc.contributor.authorDigilio, MC
dc.contributor.authorDixit, A
dc.contributor.authorEdwards, M
dc.contributor.authorFriedman, JM
dc.contributor.authorGonzalez-Meneses, A
dc.contributor.authorJoss, S
dc.contributor.authorKerr, B
dc.contributor.authorLampe, AK
dc.contributor.authorLanglois, S
dc.contributor.authorLennon, R
dc.contributor.authorLoget, P
dc.contributor.authorMa, DYT
dc.contributor.authorMcGowan, R
dc.contributor.authorDes Medt, M
dc.contributor.authorO'Sullivan, J
dc.contributor.authorOdent, S
dc.contributor.authorParker, MJ
dc.contributor.authorPebrel-Richard, C
dc.contributor.authorPetit, F
dc.contributor.authorStark, Z
dc.contributor.authorStockler-Ipsiroglu, S
dc.contributor.authorTinschert, S
dc.contributor.authorVasudevan, P
dc.contributor.authorVilla, O
dc.contributor.authorWhite, SM
dc.contributor.authorZahir, FR
dc.contributor.authorWoolf, AS
dc.contributor.authorBanka, S
dc.date.accessioned2020-12-18T02:46:51Z
dc.date.available2020-12-18T02:46:51Z
dc.date.issued2017-12-07
dc.identifierpii: S0002-9297(17)30459-7
dc.identifier.citationCuvertino, S., Stuart, H. M., Chandler, K. E., Roberts, N. A., Armstrong, R., Bernardini, L., Bhaskar, S., Callewaert, B., Clayton-Smith, J., Hernando Davalillo, C., Deshpande, C., Devriendt, K., Digilio, M. C., Dixit, A., Edwards, M., Friedman, J. M., Gonzalez-Meneses, A., Joss, S., Kerr, B. ,... Banka, S. (2017). ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder. AMERICAN JOURNAL OF HUMAN GENETICS, 101 (6), pp.1021-1033. https://doi.org/10.1016/j.ajhg.2017.11.006.
dc.identifier.issn0002-9297
dc.identifier.urihttp://hdl.handle.net/11343/255493
dc.description.abstractACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.
dc.languageEnglish
dc.publisherCELL PRESS
dc.titleACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder
dc.typeJournal Article
dc.identifier.doi10.1016/j.ajhg.2017.11.006
melbourne.affiliation.departmentPaediatrics (RCH)
melbourne.source.titleAmerican Journal of Human Genetics
melbourne.source.volume101
melbourne.source.issue6
melbourne.source.pages1021-1033
dc.rights.licenseCC BY
melbourne.elementsid1284871
melbourne.contributor.authorStark, Zornitza
melbourne.contributor.authorWhite, Susan
dc.identifier.eissn1537-6605
melbourne.accessrightsOpen Access


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record