ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder
<p dir="ltr"><i>ACTB</i> 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, sensorine...
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2017
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| _version_ | 1864513512302182400 |
|---|---|
| author | Sara Cuvertino (18892069) |
| author2 | Helen M. Stuart (12563350) Kate E. Chandler (18892072) Neil A. Roberts (12910496) Ruth Armstrong (18892075) Laura Bernardini (18892078) Sanjeev Bhaskar (3440021) Bert Callewaert (526777) Jill Clayton-Smith (2636653) Cristina Hernando Davalillo (18892081) Charu Deshpande (210571) Koenraad Devriendt (264256) Maria C. Digilio (18892084) Abhijit Dixit (7813040) Matthew Edwards (44866) Jan M. Friedman (11252261) Antonio Gonzalez-Meneses (18518244) Shelagh Joss (4260136) Bronwyn Kerr (18892087) Anne Katrin Lampe (18892090) Sylvie Langlois (3513848) Rachel Lennon (3393728) Philippe Loget (257857) David Y.T. Ma (18892093) Ruth McGowan (3374372) Maryse Des Medt (18892096) James O’Sullivan (7867148) Sylvie Odent (689615) Michael J. Parker (18892099) Céline Pebrel-Richard (13179424) Florence Petit (4260166) Zornitza Stark (8128434) Sylvia Stockler-Ipsiroglu (5467676) Sigrid Tinschert (483418) Pradeep Vasudevan (122294) Olaya Villa (18892102) Susan M. White (18892105) Farah R. Zahir (18892108) Adrian S. Woolf (9218813) Siddharth Banka (8432901) |
| author2_role | author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| author_facet | Sara Cuvertino (18892069) Helen M. Stuart (12563350) Kate E. Chandler (18892072) Neil A. Roberts (12910496) Ruth Armstrong (18892075) Laura Bernardini (18892078) Sanjeev Bhaskar (3440021) Bert Callewaert (526777) Jill Clayton-Smith (2636653) Cristina Hernando Davalillo (18892081) Charu Deshpande (210571) Koenraad Devriendt (264256) Maria C. Digilio (18892084) Abhijit Dixit (7813040) Matthew Edwards (44866) Jan M. Friedman (11252261) Antonio Gonzalez-Meneses (18518244) Shelagh Joss (4260136) Bronwyn Kerr (18892087) Anne Katrin Lampe (18892090) Sylvie Langlois (3513848) Rachel Lennon (3393728) Philippe Loget (257857) David Y.T. Ma (18892093) Ruth McGowan (3374372) Maryse Des Medt (18892096) James O’Sullivan (7867148) Sylvie Odent (689615) Michael J. Parker (18892099) Céline Pebrel-Richard (13179424) Florence Petit (4260166) Zornitza Stark (8128434) Sylvia Stockler-Ipsiroglu (5467676) Sigrid Tinschert (483418) Pradeep Vasudevan (122294) Olaya Villa (18892102) Susan M. White (18892105) Farah R. Zahir (18892108) Adrian S. Woolf (9218813) Siddharth Banka (8432901) |
| author_role | author |
| dc.creator.none.fl_str_mv | Sara Cuvertino (18892069) Helen M. Stuart (12563350) Kate E. Chandler (18892072) Neil A. Roberts (12910496) Ruth Armstrong (18892075) Laura Bernardini (18892078) Sanjeev Bhaskar (3440021) Bert Callewaert (526777) Jill Clayton-Smith (2636653) Cristina Hernando Davalillo (18892081) Charu Deshpande (210571) Koenraad Devriendt (264256) Maria C. Digilio (18892084) Abhijit Dixit (7813040) Matthew Edwards (44866) Jan M. Friedman (11252261) Antonio Gonzalez-Meneses (18518244) Shelagh Joss (4260136) Bronwyn Kerr (18892087) Anne Katrin Lampe (18892090) Sylvie Langlois (3513848) Rachel Lennon (3393728) Philippe Loget (257857) David Y.T. Ma (18892093) Ruth McGowan (3374372) Maryse Des Medt (18892096) James O’Sullivan (7867148) Sylvie Odent (689615) Michael J. Parker (18892099) Céline Pebrel-Richard (13179424) Florence Petit (4260166) Zornitza Stark (8128434) Sylvia Stockler-Ipsiroglu (5467676) Sigrid Tinschert (483418) Pradeep Vasudevan (122294) Olaya Villa (18892102) Susan M. White (18892105) Farah R. Zahir (18892108) Adrian S. Woolf (9218813) Siddharth Banka (8432901) |
| dc.date.none.fl_str_mv | 2017-12-01T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.ajhg.2017.11.006 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/ACTB_Loss-of-Function_Mutations_Result_in_a_Pleiotropic_Developmental_Disorder/26114959 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences ACTB β-actin malformations developmental disorder chromatin |
| dc.title.none.fl_str_mv | ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr"><i>ACTB</i> 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 <i>ACTB</i> mutations have not been proven conclusively. We describe heterozygous <i>ACTB</i> 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. <i>ACTB</i> 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 <i>ACTB</i> siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that <i>ACTB</i> 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 <i>ACTB</i> 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.</p><h2>Other Information</h2><p dir="ltr">Published in: The American Journal of Human Genetics<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.ajhg.2017.11.006" target="_blank">https://dx.doi.org/10.1016/j.ajhg.2017.11.006</a></p><p dir="ltr"><br></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_d63692d2f63106f79f6c9021fbf2f894 |
| identifier_str_mv | 10.1016/j.ajhg.2017.11.006 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26114959 |
| publishDate | 2017 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental DisorderSara Cuvertino (18892069)Helen M. Stuart (12563350)Kate E. Chandler (18892072)Neil A. Roberts (12910496)Ruth Armstrong (18892075)Laura Bernardini (18892078)Sanjeev Bhaskar (3440021)Bert Callewaert (526777)Jill Clayton-Smith (2636653)Cristina Hernando Davalillo (18892081)Charu Deshpande (210571)Koenraad Devriendt (264256)Maria C. Digilio (18892084)Abhijit Dixit (7813040)Matthew Edwards (44866)Jan M. Friedman (11252261)Antonio Gonzalez-Meneses (18518244)Shelagh Joss (4260136)Bronwyn Kerr (18892087)Anne Katrin Lampe (18892090)Sylvie Langlois (3513848)Rachel Lennon (3393728)Philippe Loget (257857)David Y.T. Ma (18892093)Ruth McGowan (3374372)Maryse Des Medt (18892096)James O’Sullivan (7867148)Sylvie Odent (689615)Michael J. Parker (18892099)Céline Pebrel-Richard (13179424)Florence Petit (4260166)Zornitza Stark (8128434)Sylvia Stockler-Ipsiroglu (5467676)Sigrid Tinschert (483418)Pradeep Vasudevan (122294)Olaya Villa (18892102)Susan M. White (18892105)Farah R. Zahir (18892108)Adrian S. Woolf (9218813)Siddharth Banka (8432901)Biomedical and clinical sciencesClinical sciencesACTBβ-actinmalformationsdevelopmental disorderchromatin<p dir="ltr"><i>ACTB</i> 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 <i>ACTB</i> mutations have not been proven conclusively. We describe heterozygous <i>ACTB</i> 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. <i>ACTB</i> 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 <i>ACTB</i> siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that <i>ACTB</i> 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 <i>ACTB</i> 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.</p><h2>Other Information</h2><p dir="ltr">Published in: The American Journal of Human Genetics<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.ajhg.2017.11.006" target="_blank">https://dx.doi.org/10.1016/j.ajhg.2017.11.006</a></p><p dir="ltr"><br></p>2017-12-01T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.ajhg.2017.11.006https://figshare.com/articles/journal_contribution/ACTB_Loss-of-Function_Mutations_Result_in_a_Pleiotropic_Developmental_Disorder/26114959CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/261149592017-12-01T00:00:00Z |
| spellingShingle | ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder Sara Cuvertino (18892069) Biomedical and clinical sciences Clinical sciences ACTB β-actin malformations developmental disorder chromatin |
| status_str | publishedVersion |
| title | ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder |
| title_full | ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder |
| title_fullStr | ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder |
| title_full_unstemmed | ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder |
| title_short | ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder |
| title_sort | ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder |
| topic | Biomedical and clinical sciences Clinical sciences ACTB β-actin malformations developmental disorder chromatin |