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ACTB loss-of-function mutations result in a pleiotropic developmental disorder

(2017) AMERICAN JOURNAL OF HUMAN GENETICS. 101(6). p.1021-1033
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Abstract
ACTB encodes beta-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, beta-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 beta-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, beta-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.
Keywords
WINTER CEREBROFRONTOFACIAL SYNDROME, DE-NOVO MUTATIONS, NUCLEAR ACTIN, BETA-ACTIN, DELAY, DYNAMICS, MALFORMATIONS, CYTOSKELETON, ARCHITECTURE, MECHANICS

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Citation

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Chicago
Cuvertino, Sara, Helen M Stuart, Kate E Chandler, Neil A Roberts, Ruth Armstrong, Laura Bernardini, Sanjeev Bhaskar, et al. 2017. “ACTB Loss-of-function Mutations Result in a Pleiotropic Developmental Disorder.” American Journal of Human Genetics 101 (6): 1021–1033.
APA
Cuvertino, S., Stuart, H. M., Chandler, K. E., Roberts, N. A., Armstrong, R., Bernardini, L., Bhaskar, S., et al. (2017). ACTB loss-of-function mutations result in a pleiotropic developmental disorder. AMERICAN JOURNAL OF HUMAN GENETICS, 101(6), 1021–1033.
Vancouver
1.
Cuvertino S, Stuart HM, Chandler KE, Roberts NA, Armstrong R, Bernardini L, et al. ACTB loss-of-function mutations result in a pleiotropic developmental disorder. AMERICAN JOURNAL OF HUMAN GENETICS. 2017;101(6):1021–33.
MLA
Cuvertino, Sara, Helen M Stuart, Kate E Chandler, et al. “ACTB Loss-of-function Mutations Result in a Pleiotropic Developmental Disorder.” AMERICAN JOURNAL OF HUMAN GENETICS 101.6 (2017): 1021–1033. Print.
@article{8551653,
  abstract     = {ACTB encodes beta-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, beta-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 beta-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, beta-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.},
  author       = {Cuvertino, Sara and Stuart, Helen M and Chandler, Kate E and Roberts, Neil A and Armstrong, Ruth and Bernardini, Laura and Bhaskar, Sanjeev and Callewaert, Bert and Clayton-Smith, Jill and Hernando Davalillo, Cristina and Deshpande, Charu and Devriendt, Koenraad and Digilio, Maria C and Dixit, Abhijit and Edwards, Matthew and Friedman, Jan M and Gonzalez-Meneses, Antonio and Joss, Shelagh and Kerr, Bronwyn and Lampe, Anne Katrin and Langlois, Sylvie and Lennon, Rachel and Loget, Philippe and Ma, David YT and McGowan, Ruth and Des Medt, Maryse and O'Sullivan, James and Odent, Sylvie and Parker, Michael J and Pebrel-Richard, Celine and Petit, Florence and Stark, Zornitza and Stockler-Ipsiroglu, Sylvia and Tinschert, Sigrid and Vasudevan, Pradeep and Villa, Olaya and White, Susan M and Zahir, Farah R and Woolf, Adrian S and Banka, Siddharth},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  language     = {eng},
  number       = {6},
  pages        = {1021--1033},
  title        = {ACTB loss-of-function mutations result in a pleiotropic developmental disorder},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2017.11.006},
  volume       = {101},
  year         = {2017},
}

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