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A syndromic neurodevelopmental disorder caused by mutations in SMARCD1, a core SWI/SNF subunit needed for context-dependent neuronal gene regulation in flies

A syndromic neurodevelopmental disorder caused by mutations in SMARCD1, a core SWI/SNF subunit needed for context-dependent neuronal gene regulation in flies
A syndromic neurodevelopmental disorder caused by mutations in SMARCD1, a core SWI/SNF subunit needed for context-dependent neuronal gene regulation in flies
Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on 5 individuals with mutations in SMARCD1, presenting with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. The mutations were proven to be de novo in 4 of the 5 individuals, by trio exome sequencing. Mutations in other SWI/SNF components cause Coffin-Siris syndrome and Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack the typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog, Bap60, in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom body specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify a NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development that is essential in establishing neuronal circuits that are required for learning and memory.
0002-9297
596-610
Nixon, Kevin C.J.
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Rousseau, Justine
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Stone, Max H.
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Sarikahya, Mohammed
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Ehresmann, Sophie
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Mizuno, Seiji
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Matsumoto, Naomichi
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Miyaka, Noriko
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Baralle, Diana
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McKee, Shane
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Izumi, Kosuke
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Ritter, Alyssa
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Heide, Solveig
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Héron, Delphine
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Depienne, Christel
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Titheradge, Hannah
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Kramer, Jamie M.
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Campeau, Philippe M.
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Nixon, Kevin C.J.
296a4f87-15b2-4bd0-b320-2d3354b60fd1
Rousseau, Justine
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Stone, Max H.
175eb784-ff3d-49ec-933b-29e56def9e7f
Sarikahya, Mohammed
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Ehresmann, Sophie
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Mizuno, Seiji
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Matsumoto, Naomichi
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Miyaka, Noriko
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Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
McKee, Shane
697d9bc8-c8dd-43dd-b829-1f4bcf0c2c82
Izumi, Kosuke
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Ritter, Alyssa
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Heide, Solveig
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Héron, Delphine
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Depienne, Christel
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Titheradge, Hannah
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Kramer, Jamie M.
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Campeau, Philippe M.
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Nixon, Kevin C.J., Rousseau, Justine, Stone, Max H., Sarikahya, Mohammed, Ehresmann, Sophie, Mizuno, Seiji, Matsumoto, Naomichi, Miyaka, Noriko, Baralle, Diana, McKee, Shane, Izumi, Kosuke, Ritter, Alyssa, Heide, Solveig, Héron, Delphine, Depienne, Christel, Titheradge, Hannah, Kramer, Jamie M. and Campeau, Philippe M. (2019) A syndromic neurodevelopmental disorder caused by mutations in SMARCD1, a core SWI/SNF subunit needed for context-dependent neuronal gene regulation in flies. The American Journal of Human Genetics, 104 (4), 596-610. (doi:10.1016/j.ajhg.2019.02.001).

Record type: Article

Abstract

Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on 5 individuals with mutations in SMARCD1, presenting with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. The mutations were proven to be de novo in 4 of the 5 individuals, by trio exome sequencing. Mutations in other SWI/SNF components cause Coffin-Siris syndrome and Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack the typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog, Bap60, in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom body specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify a NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development that is essential in establishing neuronal circuits that are required for learning and memory.

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Accepted/In Press date: 31 January 2019
e-pub ahead of print date: 12 March 2019
Published date: 4 April 2019

Identifiers

Local EPrints ID: 428162
URI: https://eprints.soton.ac.uk/id/eprint/428162
ISSN: 0002-9297
PURE UUID: 8d58b716-a4e7-4f8e-9628-6c049d5da808
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

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Date deposited: 13 Feb 2019 17:30
Last modified: 19 Jul 2019 16:42

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Contributors

Author: Kevin C.J. Nixon
Author: Justine Rousseau
Author: Max H. Stone
Author: Mohammed Sarikahya
Author: Sophie Ehresmann
Author: Seiji Mizuno
Author: Naomichi Matsumoto
Author: Noriko Miyaka
Author: Diana Baralle ORCID iD
Author: Shane McKee
Author: Kosuke Izumi
Author: Alyssa Ritter
Author: Solveig Heide
Author: Delphine Héron
Author: Christel Depienne
Author: Hannah Titheradge
Author: Jamie M. Kramer
Author: Philippe M. Campeau

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