Human Disease Model Report: Brunet-Wagner neurodevelopmental syndrome

General Information

Name

Brunet-Wagner neurodevelopmental syndrome

FlyBase ID

FBhh0001637

Disease Ontology Term

Brunet-Wagner neurodevelopmental syndrome

Parent Disease

OMIM

BRUNET-WAGNER NEURODEVELOPMENTAL SYNDROME; BRUWAG

Overview

This report describes Brunet-Wagner neurodevelopmental syndrome, an autosomal recessive disorder characterized by infantile hypotonia and severely impaired development affecting both motor and cognitive skills. The human gene implicated in this disease is RBL2, a member of the retinoblastoma family of proteins. There is one high-scoring fly ortholog, Dmel\Rbf, for which multiple genetic reagents, including amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

The human gene RBL2 has not been introduced into flies.

Homozygous null mutations of Dmel\Rbf are embryonic lethal. Hypomorphic Dmel\Rbf mutants exhibit smaller but structurally normal eyes, and decreased optic lobe size. Larval brains exhibit a increased number of apoptotic cells leading to significantly decreased brain size compared to wild-type controls. Mutants also exhibit developmental delay, motor defects and impaired sleep. Pan-neuronal RNAi knockdown of Dmel\Rbf results in severe behavioral defects. Knockdown in glutamatergic neurons results in a significant decline in locomotor activity.

[updated June 2025 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: Brunet-Wagner neurodevelopmental syndrome

OMIM report

[BRUNET-WAGNER NEURODEVELOPMENTAL SYNDROME; BRUWAG](https://omim.org/entry/619690)

Human gene(s) implicated

[RB TRANSCRIPTIONAL COREPRESSOR-LIKE 2; RBL2](https://omim.org/entry/180203)

Symptoms and phenotype

Of a cohort of 35 individuals bearing loss-of-function variants in the RBL2 gene, 85% exhibited postnatal microcephaly (Aughey, et al., 2025, pubmed:39692517; FBrf0262039).

(FlyBase Curators, 2013-)

Brunet-Wagner neurodevelopmental syndrome (BRUWAG) is an autosomal recessive disorder characterized by infantile hypotonia and severely impaired development affecting both motor and cognitive skills. Affected individuals either do not achieve independent ambulation or walk with an unsteady gait; those who walk may lose the ability due to spasticity of the lower limbs. They have absent language, poor or absent social skills, and behavioral abnormalities. Most have variable ocular findings, including nystagmus, strabismus, optic atrophy, myopia, or hypermetropia (summary by Brunet et al., 2020, pubmed:32105419 and Samra et al., 2021, pubmed:33980986). [from MIM:619690; 2025.06.10]

(OMIM, 2013-)

Genetics

Brunet-Wagner neurodevelopmental syndrome (BRUWAG) is caused by homozygous or compound heterozygous mutation in the RBL2 gene on chromosome 16q12. [from MIM:619690; 2025.06.10]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

The RBL2 gene encodes a member of the retinoblastoma (RB) family of proteins that mediates gene expression and regulates the cell cycle by direct binding to the E2F family of transcription factors, histone deacetylases, and additional factors (summary by Samra et al., 2021, pubmed:33980986). [from MIM:180203; 2025.06.10]

(OMIM, 2013-)

External links

Gene2Function (human gene): RBL2
Gene Cards: RBL2
MedlinePlus (gene): RBL2
MARRVEL (human gene): RBL2
NCBI MedGen: Brunet-Wagner neurodevelopmental syndrome (BRUWAG)
NCBI (Entrez) gene: RBL2; RB transcriptional corepressor like 2

Disease synonyms

BRUWAG

Related Diseases

Related human health report(s)

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

RBL2; RB transcriptional corepressor like 2

D. melanogaster ortholog (based on DIOPT)

Dmel\Rbf

(DIOPT, 2013-)

Dmel\Rbf2

(DIOPT, 2013-)

Comments on ortholog(s)

Many to two (many human to 2 Drosophila); RBL2 has one high-scoring Drosophila ortholog, Rbf, and one moderate scoring ortholog, Rbf2.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (2)

Dmel\Rbf

Gene Snapshot

Retinoblastoma-family protein (Rbf) encodes a protein that binds to members of the E2F transcription factors and forms the DREAM complex, which regulates genes with diverse biological functions including cell cycle regulators, apoptosis regulators, and DNA replication/repair factors. The product of Rbf can also bind chromosomal proteins and modulate genome stability. It is negatively regulated by CycE-Cdk2 and CycD-Cdk4 cyclin-dependent kinase complexes. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

DRM-R

Comments on ortholog(s)

High-scoring ortholog of human RBL1 and RBL2, moderate scoring ortholog of human RB1 (2 Drosophila to many human).

Orthologs and Alignments from DRSC

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

H. sapiens (Human)

Dmel\Rbf2

Gene Snapshot

Retinoblastoma-family protein 2 (Rbf2) encodes a transcriptional repressor belonging to the retinoblastoma family. It is mainly known for its role in repressing cell-cycle genes, but can also attenuate expression of other housekeeping genes, as-well as cell type specific enhancers. [Date last reviewed: 2023-09-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

DRM-R2
DRM-R

Comments on ortholog(s)

Moderate-scoring ortholog of human RBL1, RBL2, and RB1 (2 Drosophila to many human).

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 (40 groups)

Rbf

protein-protein

Interacting group

Assay

References

Rbf - bun

two hybrid array

(Shokri et al., 2019)

Rbf - Caf1-55

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

(Lee et al., 2012, Korenjak et al., 2004, Taylor-Harding et al., 2004)

Rbf - Cap-D3

anti tag coimmunoprecipitation, western blot

(Longworth et al., 2008)

Rbf - CG8089

two hybrid array

(Shokri et al., 2019)

Rbf - Cp190

anti bait coimmunoprecipitation, western blot

(Korenjak et al., 2014)

Rbf - CrebB

two hybrid array

(Shokri et al., 2019)

Rbf - Dp

anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot, coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014, Shibutani et al., 2007, Korenjak et al., 2004, Taylor-Harding et al., 2004, Weng et al., 2003, Du et al., 1996)

Rbf - E2f1

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, pull down, autoradiography, peptide massfingerprinting, experimental knowledge based, coimmunoprecipitation, two hybrid

(Kim et al., 2018, Rhee et al., 2014, Ran et al., 2013, Davidson and Duronio, 2012, Acharya et al., 2010, Ahlander et al., 2008, Lu et al., 2007, Shibutani et al., 2007, Taylor-Harding et al., 2004, Weng et al., 2003, Du et al., 1996)

Rbf - E2f2

pull down, autoradiography, anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based, western blot, anti bait coimmunoprecipitation, anti tag western blot

(Rhee et al., 2014, Lee et al., 2012, Nicolay et al., 2011, Acharya et al., 2010, Korenjak et al., 2004, Taylor-Harding et al., 2004)

Rbf - E(z)

anti bait coimmunoprecipitation, anti tag western blot

(Lee et al., 2010)

Rbf - ebi

anti tag coimmunoprecipitation, anti tag western blot

(Lim et al., 2013)

Rbf - fkh

two hybrid array

(Shokri et al., 2019)

Rbf - glu

anti tag coimmunoprecipitation, western blot

(Longworth et al., 2008)

Rbf - HDAC1

anti tag coimmunoprecipitation, western blot

(Taylor-Harding et al., 2004)

Rbf - lin-52

anti tag coimmunoprecipitation, western blot

(Lewis et al., 2012)

Rbf - mip40

affinity chromatography technology, western blot, anti bait coimmunoprecipitation, Identification by mass spectrometry

(Beall et al., 2007, Korenjak et al., 2004)

Rbf - mip120

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

(Korenjak et al., 2004, Lewis et al., 2004)

Rbf - mip130

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

(Korenjak et al., 2004, Lewis et al., 2004)

Rbf - Myb

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

(Korenjak et al., 2004, Lewis et al., 2004)

Rbf - Orc1

pull down, western blot

(Bosco et al., 2001)

Rbf - Orc2

fluorescent resonance energy transfer, fluorescence microscopy, anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot

(Ahlander et al., 2008, Bosco et al., 2001)

Rbf - sqd

anti tag coimmunoprecipitation, western blot, multidimensional protein identification technology, anti bait coimmunoprecipitation

(Ahlander and Bosco, 2009)

Rbf - Trl

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

(Bayarmagnai et al., 2012)

Rbf - twi

two hybrid array

(Shokri et al., 2019)

Rbf - Ubi-p5E

anti tag coimmunoprecipitation, anti tag western blot

(Raj et al., 2012)

Rbf - Ubi-p63E

anti tag coimmunoprecipitation, anti tag western blot

(Raj et al., 2012)

Rbf - yki

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

(Rader et al., 2023)

Rbf2

protein-protein

Interacting group

Assay

References

Rbf2 - Caf1-55

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

(Korenjak et al., 2004, Taylor-Harding et al., 2004)

Rbf2 - chinmo

two hybrid array

(Shokri et al., 2019)

Rbf2 - Dp

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

(Korenjak et al., 2004, Taylor-Harding et al., 2004)

Rbf2 - E2f2

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

(Korenjak et al., 2004, Taylor-Harding et al., 2004)

Rbf2 - E(z)

anti bait coimmunoprecipitation, anti tag western blot

(Lee et al., 2010)

Rbf2 - Ets21C

two hybrid array

(Shokri et al., 2019)

Rbf2 - HDAC1

anti tag coimmunoprecipitation, western blot

(Taylor-Harding et al., 2004)

Rbf2 - Hr78

two hybrid array

(Shokri et al., 2019)

Rbf2 - lin-52

anti tag coimmunoprecipitation, western blot

(Lewis et al., 2012)

Rbf2 - mip40

anti bait coimmunoprecipitation, western blot, Identification by mass spectrometry

(Beall et al., 2007, Korenjak et al., 2004)

Rbf2 - mip120

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

(Korenjak et al., 2004, Lewis et al., 2004)

Rbf2 - mip130

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

(Korenjak et al., 2004, Lewis et al., 2004)

Rbf2 - Myb

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

(Korenjak et al., 2004, Lewis et al., 2004)

Alleles Reported to Model Human Disease (Disease Ontology) (7 alleles)

Rbf

Models Based on Experimental Evidence ( 4 )

Allele

Disease

Evidence

References

Rbf^280.UAS

model of prostate cancer

CEA

(Sekar et al., 2023)

Rbf^15aΔ

model of cancer

CEA

(Sheng and Du, 2020)

Rbf^HMS03004

model of cancer

CEA

(Parkhitko et al., 2021)

CEA with Pten^HMS00044, Ras85D^G13Q.UAS

(Parkhitko et al., 2021)

Rbf^{Δ728-786.UAS}

model of cancer

CEA

(Elenbaas et al., 2015)

Modifiers Based on Experimental Evidence ( 5 )

Allele

Disease

Interaction

References

Rbf^UAS.cDa

ameliorates Parkinson's disease

modeled by Lrrk^I1915T.UAS

(Gehrke et al., 2010)

ameliorates brain glioma

modeled by btl::Egfr^λ.UAS, Pi3K92E^{UAS.Tag:MYC,Tag:PM(hKRAS)}

(Read et al., 2009)

ameliorates tauopathy

modeled by dap^UAS.cdNa, Hsap\MAPT^R406W.UAS

(Khurana et al., 2006)

Rbf^GD4484

exacerbates brain glioma

modeled by btl::Egfr^λ.UAS, Pi3K92E^{UAS.Tag:MYC,Tag:PM(hKRAS)}

(Read et al., 2009)

exacerbates cancer

modeled by Myc^UAS.cZa, p53^{RNAi.UAS.RasG12D}

(Diaz et al., 2024)

Rbf^GMR.PU

ameliorates viral infectious disease

modeled by EBV\BRLF1^GMR.PA

(Adamson and Lajeunesse, 2012)

ameliorates infectious mononucleosis

modeled by EBV\BRLF1^GMR.PA

(Adamson and Lajeunesse, 2012)

ameliorates Epstein-Barr virus hepatitis

modeled by EBV\BRLF1^GMR.PA

(Adamson and Lajeunesse, 2012)

Rbf^15aΔ

model of cancer

is ameliorated by psidin^AE

(Sheng and Du, 2020)

is ameliorated by psidin^55D4

(Sheng and Du, 2020)

is ameliorated by psidin^85D1

(Sheng and Du, 2020)

is ameliorated by psidin^CJ

(Sheng and Du, 2020)

Rbf^HMS03004

model of cancer

is exacerbated by Blos2^HMJ21554

(Parkhitko et al., 2021)

is exacerbated by CG10600^HMS05767

(Parkhitko et al., 2021)

is exacerbated by CG16903^HMC06024

(Parkhitko et al., 2021)

is exacerbated by CG31871^HMS05379

(Parkhitko et al., 2021)

is exacerbated by CG6015^HMS01037

(Parkhitko et al., 2021)

is exacerbated by Nkap^HMS00995

(Parkhitko et al., 2021)

is exacerbated by CG7483^HMS00696

(Parkhitko et al., 2021)

is exacerbated by Cdc27^HM04024

(Parkhitko et al., 2021)

is exacerbated by Cdc5^HMC04732

(Parkhitko et al., 2021)

is exacerbated by HDAC1^JF01401

(Parkhitko et al., 2021)

is exacerbated by α-Spec^HMC04371

(Parkhitko et al., 2021)

is exacerbated by Ada2a^HMJ03126

(Parkhitko et al., 2021)

is exacerbated by Cse1^JF02972

(Parkhitko et al., 2021)

is exacerbated by Cul3^HMS01572

(Parkhitko et al., 2021)

is exacerbated by Cul4^HMC02981

(Parkhitko et al., 2021)

is exacerbated by CycA^JF02472

(Parkhitko et al., 2021)

is exacerbated by Dim1^HMC03851

(Parkhitko et al., 2021)

is exacerbated by Hsc70-1^HMS00888

(Parkhitko et al., 2021)

is exacerbated by Dis3^HMJ24000

(Parkhitko et al., 2021)

is exacerbated by Hsc70-4^HMS00152

(Parkhitko et al., 2021)

is exacerbated by RpS4^HMS05869

(Parkhitko et al., 2021)

is exacerbated by Dlg5^HMJ23170

(Parkhitko et al., 2021)

is exacerbated by KCNQ^JF02562

(Parkhitko et al., 2021)

is exacerbated by Rpn8^HMS05743

(Parkhitko et al., 2021)

is exacerbated by Kdm5^HM05155

(Parkhitko et al., 2021)

is exacerbated by Rpn9^HMS01007

(Parkhitko et al., 2021)

is exacerbated by Sce^HMS05745

(Parkhitko et al., 2021)

is exacerbated by E(Pc)^JF03101

(Parkhitko et al., 2021)

is exacerbated by Mfap1^HM05216

(Parkhitko et al., 2021)

is exacerbated by Mi-2^HMS00301

(Parkhitko et al., 2021)

is exacerbated by Nipped-B^HM05172

(Parkhitko et al., 2021)

is exacerbated by Sec31^HMS00666

(Parkhitko et al., 2021)

is exacerbated by VhaAC39-1^HMS01442

(Parkhitko et al., 2021)

is exacerbated by SkpA^HMS00791

(Parkhitko et al., 2021)

is exacerbated by Non1^JF01590

(Parkhitko et al., 2021)

is exacerbated by SmF^JF02276

(Parkhitko et al., 2021)

is exacerbated by dom^HMS02208

(Parkhitko et al., 2021)

is exacerbated by Not1^HMS00526

(Parkhitko et al., 2021)

is exacerbated by eIF3m^HMS00667

(Parkhitko et al., 2021)

is exacerbated by Pgam1^HMC04818

(Parkhitko et al., 2021)

is exacerbated by Snap29^JF01883

(Parkhitko et al., 2021)

is exacerbated by Pp1-87B^HMS00409

(Parkhitko et al., 2021)

is exacerbated by Spt6^HMS00364

(Parkhitko et al., 2021)

is exacerbated by eIF4G1^HMS00762

(Parkhitko et al., 2021)

is exacerbated by Pp2A-29B^JF03316

(Parkhitko et al., 2021)

is exacerbated by gpp^JF01283

(Parkhitko et al., 2021)

is exacerbated by Su(H)^HMS05748

(Parkhitko et al., 2021)

is exacerbated by Su(var)2-10^HMS00750

(Parkhitko et al., 2021)

is exacerbated by Pp4-19C^HMJ21831

(Parkhitko et al., 2021)

is exacerbated by Sumo^JF02869

(Parkhitko et al., 2021)

is exacerbated by jub^HMS02335

(Parkhitko et al., 2021)

is exacerbated by kin17^HMC03906

(Parkhitko et al., 2021)

is exacerbated by kto^HMS01062

(Parkhitko et al., 2021)

is exacerbated by l(1)10Bb^HMS00255

(Parkhitko et al., 2021)

is exacerbated by Taf1^HMS00416

(Parkhitko et al., 2021)

is exacerbated by Tango1^HMS05801

(Parkhitko et al., 2021)

is exacerbated by Tlk^HMS00943

(Parkhitko et al., 2021)

is exacerbated by Prosα7^HMS00068

(Parkhitko et al., 2021)

is exacerbated by U2af38^HMS04505

(Parkhitko et al., 2021)

is exacerbated by U2af50^HMC03810

(Parkhitko et al., 2021)

is exacerbated by lqf^HMJ22079

(Parkhitko et al., 2021)

is exacerbated by Ran^HMS02885

(Parkhitko et al., 2021)

is exacerbated by mRNA-cap^HMS04494

(Parkhitko et al., 2021)

is exacerbated by U4-U6-60K^HMC03931

(Parkhitko et al., 2021)

is exacerbated by Rm62^JF01385

(Parkhitko et al., 2021)

is exacerbated by Uba1^JF01977

(Parkhitko et al., 2021)

is exacerbated by pea^HMS00528

(Parkhitko et al., 2021)

is exacerbated by RpS29^HMJ21541

(Parkhitko et al., 2021)

is exacerbated by pyd^HMS00263

(Parkhitko et al., 2021)

is exacerbated by Ubc6^HMS02466

(Parkhitko et al., 2021)

is exacerbated by qkr58E-2^HMC03966

(Parkhitko et al., 2021)

is exacerbated by sktl^JF02796

(Parkhitko et al., 2021)

is exacerbated by snRNP-U1-70K^HMS00274

(Parkhitko et al., 2021)

is exacerbated by snRNP-U1-C^HMC04045

(Parkhitko et al., 2021)

is exacerbated by sqh^HMS00437

(Parkhitko et al., 2021)

is exacerbated by sv^JF02582

(Parkhitko et al., 2021)

is exacerbated by trr^HMS01019

(Parkhitko et al., 2021)

is exacerbated by trx^HMS00580

(Parkhitko et al., 2021)

is exacerbated by tum^HMS01417

(Parkhitko et al., 2021)

is exacerbated by wapl^HMJ22638

(Parkhitko et al., 2021)

is exacerbated by wupA^JF02172

(Parkhitko et al., 2021)

is ameliorated by Naa20A^GL01093

(Sheng and Du, 2020)

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

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

w^*; P{UAS-Rbf.280}3/TM3, Sb¹

Rbf^{Δ728-786.UAS}

P{UAS-Rbf.Delta728-786}

Rbf^GMR.PU

P{GMR-Rbf.U}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

w¹¹¹⁸; P{GD4484}v10696

Rbf^HMS03004

P{TRiP.HMS03004}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS03004}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.GL01293}attP40

Rbf^HMC06195

P{TRiP.HMC06195}

y¹ sc^* v¹ sev²¹; P{TRiP.HMC06195}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.HMS01586}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.HMC06288}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Rbf¹⁴

amorphic allele - genetic evidence

Delta2-3 transposase

Rbf¹⁴ w¹¹¹⁸/FM7c

Rbf^Δ14

loss of function allele

Rbf^15aΔ

P-element activity

References (4)

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