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ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder
- Source :
- American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2017, 101 (6), pp.1021-1033. ⟨10.1016/j.ajhg.2017.11.006⟩, AMERICAN JOURNAL OF HUMAN GENETICS, Cuvertino, S, Stuart, H, Chandler, K E, Roberts, N, 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, Lampe, A K, Langlois, S, Lennon, R, Loget, P, Ma, D Y T, Ruth, M, Des Medt, M, O'Sullivan, J, Odent, S, Parker, M J, Pebrel-Richard, C, Petit, F, Stark, Z, Stockler-Ipsiroglu, S, Tinschert, S, Vasudevan, P, Villa, O, White, S M, Zahir, F R, study, T DDD, Woolf, A S & Banka, S 2017, ' ACTB loss-of-function mutations result in a pleiotropic developmental disorder ', American Journal of Human Genetics, vol. 101, no. 6, pp. 1021-1033 . https://doi.org/10.1016/j.ajhg.2017.11.006, American Journal of Human Genetics, 2017, 101 (6), pp.1021-1033. ⟨10.1016/j.ajhg.2017.11.006⟩
- Publication Year :
- 2017
- Publisher :
- HAL CCSD, 2017.
-
Abstract
- ACTB 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. ispartof: American Journal of Human Genetics vol:101 issue:6 pages:1021-1033 ispartof: location:United States status: published
- Subjects :
- DYNAMICS
Male
Developmental Disabilities
CYTOSKELETON
Haploinsufficiency
Mice
Medicine and Health Sciences
RNA, Small Interfering
Child
Frameshift Mutation
developmental disorder
ARCHITECTURE
Cell Cycle
Coloboma
Malformations of Cortical Development
Codon, Nonsense
Child, Preschool
DELAY
malformations
Female
RNA Interference
Abnormalities
Multiple
Adult
Adolescent
Small Interfering
Young Adult
WINTER CEREBROFRONTOFACIAL SYNDROME
Report
Intellectual Disability
Humans
Animals
Abnormalities, Multiple
MALFORMATIONS
β-actin
Preschool
Codon
Aged
Cell Proliferation
[SDV.GEN]Life Sciences [q-bio]/Genetics
Infant, Newborn
Biology and Life Sciences
Infant
Facies
ACTB
Newborn
NUCLEAR ACTIN
Actins
BETA-ACTIN
Nonsense
DE-NOVO MUTATIONS
MECHANICS
chromatin
RNA
Gene Deletion
Subjects
Details
- Language :
- English
- ISSN :
- 00029297 and 15376605
- Database :
- OpenAIRE
- Journal :
- American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2017, 101 (6), pp.1021-1033. ⟨10.1016/j.ajhg.2017.11.006⟩, AMERICAN JOURNAL OF HUMAN GENETICS, Cuvertino, S, Stuart, H, Chandler, K E, Roberts, N, 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, Lampe, A K, Langlois, S, Lennon, R, Loget, P, Ma, D Y T, Ruth, M, Des Medt, M, O'Sullivan, J, Odent, S, Parker, M J, Pebrel-Richard, C, Petit, F, Stark, Z, Stockler-Ipsiroglu, S, Tinschert, S, Vasudevan, P, Villa, O, White, S M, Zahir, F R, study, T DDD, Woolf, A S & Banka, S 2017, ' ACTB loss-of-function mutations result in a pleiotropic developmental disorder ', American Journal of Human Genetics, vol. 101, no. 6, pp. 1021-1033 . https://doi.org/10.1016/j.ajhg.2017.11.006, American Journal of Human Genetics, 2017, 101 (6), pp.1021-1033. ⟨10.1016/j.ajhg.2017.11.006⟩
- Accession number :
- edsair.pmid.dedup....6f609dbbe66ece9116e090ada0b0f1dc