TY - JOUR
T1 - Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity
AU - Witteveen, Josefine S.
AU - Willemsen, Marjolein H.
AU - Dombroski, Thais C. D.
AU - van Bakel, Nick H. M.
AU - Nillesen, Willy M.
AU - van Hulten, Josephus A.
AU - Jansen, Eric J. R.
AU - Verkaik, Dave
AU - Veenstra-Knol, Hermine E.
AU - van Ravenswaaij-Arts, Conny M. A.
AU - Wassink-Ruiter, Jolien S. Klein
AU - Vincent, Marie
AU - David, Albert
AU - Le Caignec, Cedric
AU - Schieving, Jolanda
AU - Gilissen, Christian
AU - Foulds, Nicola
AU - Rump, Patrick
AU - Strom, Tim
AU - Cremer, Kirsten
AU - Zink, Alexander M.
AU - Engels, Hartmut
AU - de Munnik, Sonja A.
AU - Visser, Jasper E.
AU - Brunner, Han G.
AU - Martens, Gerard J. M.
AU - Pfundt, Rolph
AU - Kleefstra, Tjitske
AU - Kolk, Sharon M.
PY - 2016/8
Y1 - 2016/8
N2 - 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.
AB - 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.
KW - DEVELOPING CEREBRAL-CORTEX
KW - 15Q24 MICRODELETION SYNDROME
KW - HISTONE DEACETYLASE COMPLEX
KW - EMBRYONIC STEM-CELLS
KW - NEURAL STEM
KW - NEURODEVELOPMENTAL DISORDERS
KW - DEVELOPING NEOCORTEX
KW - RETT-SYNDROME
KW - HUMAN BRAIN
KW - MECP2
U2 - 10.1038/ng.3619
DO - 10.1038/ng.3619
M3 - Article
VL - 48
SP - 877
EP - 887
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 8
ER -