Human Disease Model Report: intellectual developmental disorders, SMARCA2,4-related

General Information

Name

intellectual developmental disorders, SMARCA2,4-related

FlyBase ID

FBhh0001097

Disease Ontology Term

syndromic intellectual disability

Parent Disease

OMIM

Overview

This report describes a Drosophila model using the fly gene brm to model intellectual developmental disorder(s) caused by disruption of SWI/SNF complexes. Multiple genes within the SWI/SNF family have been implicated in a form of syndromic intellectual disability designated Coffin-Siris syndrome (see FBhh0001088). Dmel\brm encodes a core component of some SWI/SNF complexes; these complexes regulate transcription via chromatin remodeling. Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for brm.

There are two genes orthologous to Dmel\brm in human, SMARCA2 and SMARCA4, both of which are implicated in syndromes that include intellectual disability (see FBhh0001093 and FBhh0001096). A UAS construct of the wild-type human Hsap\SMARCA2 gene has been introduced into flies, but has not been characterized. SMARCA4 has not been introduced into flies.

Animals homozygous for loss-of-function mutations of brm die during the embryonic stage. RNAi-targeted knockdown of brm in the mushroom body (a brain region associated with learning and memory) causes male flies not to reduce courtship attempts after being rejected by a female, a measure of memory formation in flies. Both short-term and long-term memory impairment are observed. Defects in mushroom body morphology are observed, including reduced survival of MBγ axons during aging. Many physical and genetic interactions have been reported for Dmel\brm; see below and in the brm gene report.

[updated Apr. 2020 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: intellectual developmental disorders, SMARCA2,4-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

SMARCA2 and SMARCA4 encode members of the SWI/SNF family; members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by localized chromatin remodeling (alteration of DNA-nucleosome topology). [Gene Cards, SMARCA2, SMARCA4; 2019.07.22]

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): SMARCA4
Gene2Function (human gene): SMARCA2
Gene Cards: SMARCA4
Gene Cards: SMARCA2
MedlinePlus (gene): SMARCA2
MedlinePlus (gene): SMARCA4
MARRVEL (human gene): SMARCA4
MARRVEL (human gene): SMARCA2
NCBI MedGen: Mental retardation, autosomal dominant 16 (CSS4)
NCBI MedGen: Nicolaides-Baraitser syndrome (NCBRS)
NCBI (Entrez) gene: SMARCA4; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
NCBI (Entrez) gene: SMARCA2; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2

Disease synonyms

Search term: Coffin-Siris syndrome

SSRIDD

SWI/SNF-related intellectual disability disorder

Related Diseases

Related human health report(s)

Coffin-Siris syndrome

Coffin-Siris syndrome 4

neurodevelopmental syndrome with mild facial dysmorphia, SMARCA5-related

Nicolaides-Baraitser syndrome

Ortholog Information

Human gene(s) in FlyBase

Hsap\SMARCA2

Human gene (HGNC)

Symbol / Name

SMARCA2; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2

D. melanogaster ortholog (based on DIOPT)

Dmel\brm

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila.

Human gene (HGNC)

Symbol / Name

SMARCA4; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4

D. melanogaster ortholog (based on DIOPT)

Dmel\brm

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\brm

Gene Snapshot

brahma (brm) encodes the ATPase subunit of the Brahma chromatin-remodeling complex, which is involved in transcription regulation. It regulates Egfr signalling, stem cell proliferation, and innate immune response. It contributes to multiple processes including neurogenesis, muscle development, phagocytosis, His3-K27 acetylation and leg and wing morphogenesis. [Date last reviewed: 2019-03-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human SMARCA2 and SMARCA4 (1 Drosophila to 2 human). Dmel\brm shares 50-51% identity and 62-63% similarity with the human genes.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (78 groups)

brm

protein-protein

Interacting group

Assay

References

brm - Act5C

anti bait coimmunoprecipitation, ion exchange chromatography, molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot, Identification by mass spectrometry, peptide massfingerprinting, pull down, edman degradation

(Tilly et al., 2021, Hong and Choi, 2016, Mohrmann et al., 2004, Kal et al., 2000, Collins et al., 1999, Papoulas et al., 1998)

brm - Act42A

pull down, ion exchange chromatography, molecular sieving, edman degradation, anti bait coimmunoprecipitation, peptide massfingerprinting, protein cross-linking with a bifunctional reagent, Identification by mass spectrometry, molecular weight estimation by staining

(Mashtalir et al., 2018, Mohrmann et al., 2004, Kal et al., 2000, Papoulas et al., 1998)

brm - asf1

anti bait coimmunoprecipitation, western blot, pull down

(Moshkin et al., 2002)

brm - Bap26

anti bait coimmunoprecipitation, ion exchange chromatography, molecular sieving, molecular weight estimation by staining

(Kal et al., 2000)

brm - Bap55

pull down, ion exchange chromatography, molecular sieving, edman degradation, anti bait coimmunoprecipitation, molecular weight estimation by staining, peptide massfingerprinting, Identification by mass spectrometry, experimental knowledge based, anti tag coimmunoprecipitation, western blot, protein cross-linking with a bifunctional reagent, anti tag western blot

(Tilly et al., 2021, Mashtalir et al., 2018, Hong and Choi, 2016, Guruharsha et al., 2011, Mohrmann et al., 2004, Armstrong et al., 2002, Kal et al., 2000, Collins et al., 1999, Papoulas et al., 1998)

brm - Bap60

anti bait coimmunoprecipitation, western blot, pull down, ion exchange chromatography, molecular sieving, edman degradation, anti tag coimmunoprecipitation, Identification by mass spectrometry, protein cross-linking with a bifunctional reagent, peptide massfingerprinting, molecular weight estimation by staining, experimental knowledge based

(Tilly et al., 2021, Barish et al., 2020, Kuhn et al., 2019, Mashtalir et al., 2018, Nakayama et al., 2012, Guruharsha et al., 2011, Mohrmann et al., 2004, Kal et al., 2000, Collins et al., 1999, Papoulas et al., 1998)

brm - Bap111

anti bait coimmunoprecipitation, molecular weight estimation by staining, protein cross-linking with a bifunctional reagent, Identification by mass spectrometry, peptide massfingerprinting, anti tag coimmunoprecipitation, western blot, pull down, ion exchange chromatography, molecular sieving

(Tilly et al., 2021, Mashtalir et al., 2018, Mohrmann et al., 2004, Armstrong et al., 2002, Kal et al., 2000, Collins et al., 1999, Papoulas et al., 1998)

brm - Bap170

anti bait coimmunoprecipitation, western blot, Identification by mass spectrometry, ion exchange chromatography, molecular sieving, molecular weight estimation by staining, peptide massfingerprinting

(Tilly et al., 2021, Chalkley et al., 2008, Mohrmann et al., 2004, Kal et al., 2000)

brm - BCL7-like

anti bait coimmunoprecipitation, Identification by mass spectrometry

(Tilly et al., 2021)

brm - Bicra

anti tag coimmunoprecipitation, Identification by mass spectrometry, anti bait coimmunoprecipitation

(Tilly et al., 2021, Barish et al., 2020)

brm - Brd7-9

protein cross-linking with a bifunctional reagent, Identification by mass spectrometry, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation

(Tilly et al., 2021, Barish et al., 2020, Mashtalir et al., 2018)

brm - Cdk8

experimental knowledge based

(Guruharsha et al., 2011)

brm - CG10555

anti bait coimmunoprecipitation, Identification by mass spectrometry

(Tilly et al., 2021)

brm - Clk

anti tag coimmunoprecipitation, anti tag western blot, western blot, Identification by mass spectrometry

(Kwok et al., 2015, Kwok et al., 2015)

brm - Cpsf6

anti bait coimmunoprecipitation, Identification by mass spectrometry, western blot, experimental knowledge based

(Yu et al., 2018, Guruharsha et al., 2011)

brm - d4

anti bait coimmunoprecipitation, Identification by mass spectrometry, anti tag coimmunoprecipitation

(Tilly et al., 2021, Barish et al., 2020)

brm - dsh

experimental knowledge based

(Guruharsha et al., 2011)

brm - Dsor1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

brm - e(y)3

anti bait coimmunoprecipitation, Identification by mass spectrometry, anti tag coimmunoprecipitation, western blot

(Tilly et al., 2021, Vorobyeva et al., 2009, Chalkley et al., 2008)

brm - ebi

experimental knowledge based

(Guruharsha et al., 2011)

brm - EcR

proximity-dependent biotin identification, Identification by mass spectrometry, anti bait coimmunoprecipitation, western blot

(Mazina et al., 2020)

brm - Elys

anti bait coimmunoprecipitation, western blot

(Kuhn et al., 2019)

brm - enc

experimental knowledge based

(Guruharsha et al., 2011)

brm - erm

anti tag coimmunoprecipitation, anti tag western blot, pull down

(Koe et al., 2014)

brm - foxo

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

brm - geminin

anti tag coimmunoprecipitation, western blot

(Herr et al., 2010)

brm - gig

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

brm - Gtpbp2

experimental knowledge based

(Guruharsha et al., 2011)

brm - HDAC3

anti tag coimmunoprecipitation, anti tag western blot

(Koe et al., 2014)

brm - His3

pull down, western blot, Identification by mass spectrometry, anti tag western blot

(Regadas et al., 2021, Tie et al., 2012)

brm - Hsc70-4

pull down, ion exchange chromatography, molecular sieving, edman degradation

(Papoulas et al., 1998)

brm - Larp4B

experimental knowledge based

(Guruharsha et al., 2011)

brm - Lasp

two hybrid

(Hu et al., 2017.6.13)

brm - Lkb1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

brm - mael

anti tag coimmunoprecipitation, western blot

(Onishi et al., 2020)

brm - MED4

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED6

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED8

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED11

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED14

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED15

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED17

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED18

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED23

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED24

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED27

experimental knowledge based

(Guruharsha et al., 2011)

brm - MED30

experimental knowledge based

(Guruharsha et al., 2011)

brm - mle

anti bait coimmunoprecipitation, western blot

(Nikolenko et al., 2021)

brm - mor

anti bait coimmunoprecipitation, western blot, anti tag western blot, pull down, autoradiography, ion exchange chromatography, molecular sieving, molecular weight estimation by staining, Identification by mass spectrometry, far western blotting, peptide massfingerprinting, protein cross-linking with a bifunctional reagent, experimental knowledge based

(Tilly et al., 2021, Mashtalir et al., 2018, Guruharsha et al., 2011, Chalkley et al., 2008, Mohrmann et al., 2004, Kal et al., 2000, Collins et al., 1999, Crosby et al., 1999, Papoulas et al., 1998)

brm - Myc

anti bait coimmunoprecipitation, western blot

(Secombe et al., 2007)

brm - nej

molecular sieving, western blot, pull down, anti tag western blot, anti bait coimmunoprecipitation

(Tie et al., 2012)

brm - osa

anti bait coimmunoprecipitation, western blot, peptide massfingerprinting, experimental knowledge based, Identification by mass spectrometry, ion exchange chromatography, molecular sieving

(Tilly et al., 2021, Nakayama et al., 2012, Guruharsha et al., 2011, Chalkley et al., 2008, Mohrmann et al., 2004, Kal et al., 2000, Collins et al., 1999)

brm - p400

anti bait coimmunoprecipitation, ion exchange chromatography, molecular sieving, molecular weight estimation by staining

(Kal et al., 2000)

brm - piwi

anti bait coimmunoprecipitation, western blot, Identification by mass spectrometry

(Onishi et al., 2020)

brm - Polr2A

anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot

(Hong and Choi, 2016)

brm - polybromo

ion exchange chromatography, molecular sieving, western blot, anti bait coimmunoprecipitation, Identification by mass spectrometry, peptide massfingerprinting

(Tilly et al., 2021, Kuhn et al., 2019, Nakayama et al., 2012, Chalkley et al., 2008, Mohrmann et al., 2004)

brm - Psi

experimental knowledge based

(Guruharsha et al., 2011)

brm - psq

anti bait coimmunoprecipitation, western blot

(Chetverina et al., 2022)

brm - Ptip

experimental knowledge based

(Guruharsha et al., 2011)

brm - rictor

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

brm - S6kII

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

brm - sd

anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, peptide massfingerprinting

(Zhu et al., 2015, Jin et al., 2013)

brm - Sec13

anti bait coimmunoprecipitation, western blot

(Kuhn et al., 2019)

brm - sima

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

brm - Snr1

coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based, molecular weight estimation by staining, pull down, ion exchange chromatography, molecular sieving, Identification by mass spectrometry

(Tilly et al., 2021, Guruharsha et al., 2011, Mohrmann et al., 2004, Zraly et al., 2004, Marenda et al., 2003, Kal et al., 2000, Collins et al., 1999, Papoulas et al., 1998, Dingwall et al., 1995)

brm - su(Hw)

anti bait coimmunoprecipitation, western blot, full identification by DNA sequencing

(Vorobyeva et al., 2021, Matzat et al., 2013)

brm - Tctp

two hybrid, anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot

(Hong and Choi, 2016)

brm - tim

anti tag coimmunoprecipitation, anti tag western blot, western blot

(Kwok et al., 2015)

brm - Trl

anti tag coimmunoprecipitation, peptide massfingerprinting, anti bait coimmunoprecipitation, western blot

(Nakayama et al., 2012)

brm - Tsc1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

brm - tth

anti bait coimmunoprecipitation, Identification by mass spectrometry

(Tilly et al., 2021)

brm - Ubx

proximity-dependent biotin identification, Identification by mass spectrometry, anti tag coimmunoprecipitation, anti tag western blot

(Carnesecchi et al., 2020)

brm - Usp10

experimental knowledge based

(Guruharsha et al., 2011)

brm - Utx

anti bait coimmunoprecipitation, western blot, molecular sieving

(Tie et al., 2012)

brm - yki

anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, peptide massfingerprinting

(Zhu et al., 2015, Jin et al., 2013, Oh et al., 2013)

brm - z

anti bait coimmunoprecipitation, autoradiography

(Kal et al., 2000)

RNA-protein

Interacting group

Assay

References

brm - Cp190

anti bait coimmunoprecipitation, full identification by DNA sequencing

(Matzat et al., 2013)

brm - shep

electrophoretic mobility shift assay, autoradiography

(Chen et al., 2019)

brm - su(Hw)

anti bait coimmunoprecipitation, western blot, full identification by DNA sequencing

(Vorobyeva et al., 2021, Matzat et al., 2013)

Alleles Reported to Model Human Disease (Disease Ontology) (3 alleles)

brm

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

brm^GL00090

model of Nicolaides-Baraitser syndrome

CEC

(MacPherson et al., 2023)

brm^GD4507

model of opportunistic bacterial infectious disease

CEA

(Bonnay et al., 2014)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

brm^{K804R.UAS.Tag:HA}

ameliorates cancer

modeled by dlg1^HMS01954

(Bunker et al., 2015)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Hsap\SMARCA2^UAS.Tag:HA

PBac{UAS-hSMARCA2.HA}

y¹ w^*; PBac{UAS-hSMARCA2.HA}VK00037

Hsap\SMARCA2^UAS.2.Tag:HA

PBac{UAS-hSMARCA2.HA.2}

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

brm^{K804R.UAS.Tag:HA}

P{UAS-brm.K804R.T:HA1}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

w¹¹¹⁸; P{GD4507}v37720

brm^HM04019

P{TRiP.HM04019}

y¹ v¹; P{TRiP.HM04019}attP2

brm^GL00090

P{TRiP.GL00090}

y¹ sc^* v¹ sev²¹; P{TRiP.GL00090}attP2

brm^HMS00050

P{TRiP.HMS00050}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00050}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

brm²

amorphic allele - genetic evidence

ethyl methanesulfonate

brm² e^s ca¹/TM6B, Sb¹ Tb¹ ca¹

References (5)

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