TY - JOUR
T1 - ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder
AU - Cuvertino, Sara
AU - Stuart, Helen M.
AU - Chandler, Kate E.
AU - Roberts, Neil A.
AU - Armstrong, Ruth
AU - Bernardini, Laura
AU - Bhaskar, Sanjeev
AU - Callewaert, Bert
AU - Clayton-Smith, Jill
AU - Davalillo, Cristina Hernando
AU - Deshpande, Charu
AU - Devriendt, Koenraad
AU - Digilio, Maria C.
AU - Dixit, Abhijit
AU - Edwards, Matthew
AU - Friedman, Jan M.
AU - Gonzalez-Meneses, Antonio
AU - Joss, Shelagh
AU - Kerr, Bronwyn
AU - Lampe, Anne Katrin
AU - Langlois, Sylvie
AU - Lennon, Rachel
AU - Loget, Philippe
AU - Ma, David Y.T.
AU - McGowan, Ruth
AU - Des Medt, Maryse
AU - O'Sullivan, James
AU - Odent, Sylvie
AU - Parker, Michael J.
AU - Pebrel-Richard, Céline
AU - Petit, Florence
AU - Stark, Zornitza
AU - Stockler-Ipsiroglu, Sylvia
AU - Tinschert, Sigrid
AU - Vasudevan, Pradeep
AU - Villa, Olaya
AU - White, Susan M.
AU - Zahir, Farah R.
AU - Woolf, Adrian S.
AU - Banka, Siddharth
AU - The DDD Study
PY - 2017/12/7
Y1 - 2017/12/7
N2 - 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.
AB - 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.
KW - ACTB
KW - chromatin
KW - developmental disorder
KW - malformations
KW - β-actin
UR - http://www.scopus.com/inward/record.url?scp=85037332890&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85037332890&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2017.11.006
DO - 10.1016/j.ajhg.2017.11.006
M3 - Article
C2 - 29220674
AN - SCOPUS:85037332890
VL - 101
SP - 1021
EP - 1033
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -