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Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity

Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity
Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity
Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.
1061-4036
877-887
Witteveen, Josefine S.
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Willemsen, Marjolein H.
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Dombroski, Thaís C.D.
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Van Bakel, Nick H.M.
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Nillesen, Willy M
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Van Hulten, Josephus A.
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Jansen, Eric J.R.
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Verkaik, Dave
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Veenstra-Knol, Hermine E.
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Wassink-Ruiter, Jolien S. Klein
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Vincent, Marie
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David, Albert
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Le Caignec, Cedric
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Schieving, Jolanda
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Gilissen, Christian
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Foulds, Nicola
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Rump, Patrick
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Strom, Tim
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Cremer, Kirsten
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Zink, Alexander M.
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De Munnik, Sonja A.
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Visser, Jasper E.
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Brunner, Han G.
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Martens, Gerard J.M.
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Pfundt, Rolph
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Kleefstra, Tjitske
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Witteveen, Josefine S.
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Willemsen, Marjolein H.
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Dombroski, Thaís C.D.
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Van Bakel, Nick H.M.
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Nillesen, Willy M
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Van Hulten, Josephus A.
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Jansen, Eric J.R.
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Verkaik, Dave
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Veenstra-Knol, Hermine E.
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Vincent, Marie
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David, Albert
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Le Caignec, Cedric
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Schieving, Jolanda
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Gilissen, Christian
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Foulds, Nicola
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Rump, Patrick
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Strom, Tim
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Cremer, Kirsten
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Zink, Alexander M.
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Engels, Hartmut
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De Munnik, Sonja A.
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Visser, Jasper E.
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Brunner, Han G.
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Martens, Gerard J.M.
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Pfundt, Rolph
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Kolk, Sharon M.
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Witteveen, Josefine S., Willemsen, Marjolein H., Dombroski, Thaís C.D., Van Bakel, Nick H.M., Nillesen, Willy M, Van Hulten, Josephus A., Jansen, Eric J.R., Verkaik, Dave, Veenstra-Knol, Hermine E., Van Ravenswaaij-Arts, Conny M.A., Wassink-Ruiter, Jolien S. Klein, Vincent, Marie, David, Albert, Le Caignec, Cedric, Schieving, Jolanda, Gilissen, Christian, Foulds, Nicola, Rump, Patrick, Strom, Tim, Cremer, Kirsten, Zink, Alexander M., Engels, Hartmut, De Munnik, Sonja A., Visser, Jasper E., Brunner, Han G., Martens, Gerard J.M., Pfundt, Rolph, Kleefstra, Tjitske and Kolk, Sharon M. (2016) Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity. Nature Genetics, 48 (8), 877-887. (doi:10.1038/ng.3619).

Record type: Article

Abstract

Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.

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Accepted/In Press date: 15 June 2016
e-pub ahead of print date: 11 July 2016
Published date: August 2016
Organisations: Human Development & Health

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Local EPrints ID: 411152
URI: http://eprints.soton.ac.uk/id/eprint/411152
ISSN: 1061-4036
PURE UUID: 6d408161-61b0-4dae-8586-b82483d997aa

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Date deposited: 15 Jun 2017 16:31
Last modified: 06 Oct 2020 20:30

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Contributors

Author: Josefine S. Witteveen
Author: Marjolein H. Willemsen
Author: Thaís C.D. Dombroski
Author: Nick H.M. Van Bakel
Author: Willy M Nillesen
Author: Josephus A. Van Hulten
Author: Eric J.R. Jansen
Author: Dave Verkaik
Author: Hermine E. Veenstra-Knol
Author: Conny M.A. Van Ravenswaaij-Arts
Author: Jolien S. Klein Wassink-Ruiter
Author: Marie Vincent
Author: Albert David
Author: Cedric Le Caignec
Author: Jolanda Schieving
Author: Christian Gilissen
Author: Nicola Foulds
Author: Patrick Rump
Author: Tim Strom
Author: Kirsten Cremer
Author: Alexander M. Zink
Author: Hartmut Engels
Author: Sonja A. De Munnik
Author: Jasper E. Visser
Author: Han G. Brunner
Author: Gerard J.M. Martens
Author: Rolph Pfundt
Author: Tjitske Kleefstra
Author: Sharon M. Kolk

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