Human Disease Model Report: intellectual disability, KDM5-related

General Information

Name

intellectual disability, KDM5-related

FlyBase ID

FBhh0001334

Disease Ontology Term

syndromic intellectual disability

Parent Disease

OMIM

Overview

Several of the paralogous KDM5 genes in human are implicated in intellectual disability (see MIM:300534, FBhh0000849; MIM:618109, FBhh0001335). The KDM5 genes (KDM5A, KDM5B, KDM5C, and KDM5D) encode histone demethylases that specifically demethylate Lys-4 of histone H3 and act as transcriptional regulators. There is a single orthologous gene in Drosophila, Dmel\Kdm5, for which multiple genetic reagents have been generated, including an amorphic mutation, RNAi-targeting constructs, and alleles caused by insertional mutagenesis.

None of the human KDM5 genes have been introduced into flies.

Animals homozygous for a null allele of Kdm5 survive to late pupal stages but fail to eclose; pharate adults exhibit abnormalities in the mushroom bodies of the brain. It has been determined that Kdm5 is required within ganglion mother cells and immature neurons of the mushroom body for proper axogenesis. However, the mechanism by which Kdm5 functions in this context appears to be independent of its canonical histone demethylase activity. This neurodevelopmental system has been used to identify genes regulated by Kdm5.

Similar defects in the development of the mushroom bodies are observed in Drosophila disease models for intellectual disability, autosomal recessive 56 (FBhh0000602) and fragile-X syndrome (FBhh0000136).

[updated Apr. 2021 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: intellectual disability, KDM5-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

The KDM5 genes (KDM5A, KDM5B, KDM5C, and KDM5D) encode histone demethylases that specifically demethylate Lys-4 of histone H3. The KDM5 proteins act as transcriptional repressors; may also play roles in genome stability and DNA repair. [Gene Cards, KDM5B, KDM5C; 2021.04.06]

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): KDM5C
Gene2Function (human gene): KDM5B
Gene Cards: KDM5C
Gene Cards: KDM5B
MedlinePlus (gene): KDM5C
MedlinePlus (gene): KDM5B
MARRVEL (human gene): KDM5C
MARRVEL (human gene): KDM5B
NCBI MedGen: Mental retardation, syndromic, Claes-Jensen type, X-linked (MRXSCJ)
NCBI MedGen: Intellectual disability, autosomal recessive 65 (MRT65)
NCBI (Entrez) gene: KDM5C; lysine demethylase 5C
NCBI (Entrez) gene: KDM5B; lysine demethylase 5B

Disease synonyms

Related Diseases

Related human health report(s)

intellectual disability, autosomal recessive 65

intellectual disability, X-linked, syndromic, Claes-Jensen type

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

KDM5B; lysine demethylase 5B

D. melanogaster ortholog (based on DIOPT)

Dmel\Kdm5

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 4 human genes to 1 Drosophila gene.

Human gene (HGNC)

Symbol / Name

KDM5C; lysine demethylase 5C

D. melanogaster ortholog (based on DIOPT)

Dmel\Kdm5

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 4 human genes to 1 Drosophila gene.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Kdm5

Gene Snapshot

Lysine demethylase 5 (Kdm5) encodes a trimethyl H3K4 histone demethylase that regulates transcription through both demethylase-dependent and demethylase-independent mechanisms. It has roles in regulating cell growth, circadian rhythm, stress resistance, hematopoiesis and fertility. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human KDM5A, KDM5B, KDM5C and KDM5D (1 Drosophila to 4 human). Dmel\Kdm5 shares 39-42% identity and 53-57% 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 (22 groups)

Kdm5

protein-protein

Interacting group

Assay

References

Kdm5 - abd-A

bimolecular fluorescence complementation, fluorescence microscopy

(Bischof et al., 2018)

Kdm5 - asf1

anti bait coimmunoprecipitation, Identification by mass spectrometry, western blot

(Moshkin et al., 2009)

Kdm5 - ash2

anti bait coimmunoprecipitation, western blot

(Secombe et al., 2007)

Kdm5 - CG3815

anti bait coimmunoprecipitation, Identification by mass spectrometry, western blot, anti tag coimmunoprecipitation, ion exchange chromatography, molecular sieving, affinity chromatography technology

(Lee et al., 2009, Moshkin et al., 2009)

Kdm5 - CG10918

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014)

Kdm5 - CG13367

ion exchange chromatography, molecular sieving, affinity chromatography technology, Identification by mass spectrometry

(Lee et al., 2009)

Kdm5 - CG13775

two hybrid array

(Shokri et al., 2019)

Kdm5 - CG15356

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

(Moshkin et al., 2009)

Kdm5 - Ets65A

two hybrid array

(Shokri et al., 2019)

Kdm5 - foxo

pull down, autoradiography, anti tag coimmunoprecipitation, anti tag western blot

(Liu et al., 2014)

Kdm5 - HDAC1

anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, affinity chromatography technology, molecular sieving, molecular weight estimation by staining, ion exchange chromatography, Identification by mass spectrometry, anti tag western blot

(Gajan et al., 2016, Lee et al., 2009, Moshkin et al., 2009)

Kdm5 - HDAC4

anti bait coimmunoprecipitation, western blot

(Liu et al., 2014)

Kdm5 - His3

enzymatic study, peptide massfingerprinting, pull down, molecular weight estimation by staining

(Li et al., 2010, Lee et al., 2007)

Kdm5 - Hr78

two hybrid array

(Shokri et al., 2019)

Kdm5 - MRG15

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, Identification by mass spectrometry, molecular sieving, ion exchange chromatography, affinity chromatography technology

(Lee et al., 2009, Moshkin et al., 2009)

Kdm5 - Myc

anti bait coimmunoprecipitation, western blot, pull down, autoradiography

(Li et al., 2010, Secombe et al., 2007)

Kdm5 - Nap1

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

(Moshkin et al., 2009)

Kdm5 - sage

two hybrid array

(Shokri et al., 2019)

Kdm5 - Sin3A

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

(Gajan et al., 2016, Spain et al., 2010, Moshkin et al., 2009)

Kdm5 - Su(H)

anti bait coimmunoprecipitation, western blot, pull down, autoradiography

(Liefke et al., 2010, Moshkin et al., 2009)

Kdm5 - Ubx

bimolecular fluorescence complementation, fluorescence microscopy

(Bischof et al., 2018)

Kdm5 - vis

two hybrid array

(Shokri et al., 2019)

Alleles Reported to Model Human Disease (Disease Ontology) (15 alleles)

Kdm5

Models Based on Experimental Evidence ( 13 )

Allele

Disease

Evidence

References

Kdm5¹⁰⁴²⁴

model of autism spectrum disorder

CEA with Kdm5^k06801

(Chen et al., 2019)

Kdm5^k06801

model of autism spectrum disorder

CEA with Kdm5¹⁰⁴²⁴

(Chen et al., 2019)

model of alcohol use disorder

CEA

(Pinzón et al., 2017)

Kdm5^HM05155

model of autism spectrum disorder

CEA

(Chen et al., 2019)

Kdm5^GLV21071

model of syndromic intellectual disability

CEA

(Hatch et al., 2021)

model of syndromic X-linked intellectual disability Claes-Jensen type

CEA

(Yheskel et al., 2024)

Kdm5^KK102745

model of alcohol use disorder

CEA

(Pinzón et al., 2017)

Kdm5^JmjC.Tag:HA

model of intellectual disability

CEA

(Zamurrad et al., 2018)

model of syndromic X-linked intellectual disability Claes-Jensen type

CEA

(Yheskel et al., 2024, Belalcazar et al., 2021)

Kdm5¹⁴⁰

model of intellectual disability

CEA

(Yheskel et al., 2023)

model of syndromic X-linked intellectual disability Claes-Jensen type

CEA

(Belalcazar et al., 2021)

model of syndromic intellectual disability

CEA

(Hatch et al., 2021)

Kdm5^A512P.Tag:HA

model of intellectual disability

CEA

(Zamurrad et al., 2018)

Kdm5^L854F.Tag:HA

model of syndromic X-linked intellectual disability Claes-Jensen type

CEA

(Yheskel et al., 2024, Belalcazar et al., 2021)

Kdm5^R873W.Tag:HA

model of syndromic X-linked intellectual disability Claes-Jensen type

CEA

(Yheskel et al., 2024, Belalcazar et al., 2021)

Kdm5^Y874C.Tag:HA

model of syndromic X-linked intellectual disability Claes-Jensen type

CEA

(Yheskel et al., 2024, Belalcazar et al., 2021)

Kdm5^A224T.Tag:HA

model of syndromic X-linked intellectual disability Claes-Jensen type

CEA

(Yheskel et al., 2024)

Kdm5^D234G.Tag:HA

model of syndromic X-linked intellectual disability Claes-Jensen type

CEA

(Yheskel et al., 2024)

Modifiers Based on Experimental Evidence ( 5 )

Allele

Disease

Interaction

References

Kdm5¹⁰⁴²⁴

ameliorates Huntington's disease

modeled by Hsap\HTT^Q93.ex1.UAS

(Vashishtha et al., 2013)

Kdm5^HM05155

model of autism spectrum disorder

is ameliorated by imd^HMS00253

(Chen et al., 2019)

ameliorates amyotrophic lateral sclerosis type 10

modeled by Hsap\TARDBP^UAS.cEa

(Berson et al., 2017)

exacerbates cancer

modeled by Rbf^HMS03004

(Parkhitko et al., 2021)

Kdm5¹⁴⁰

model of intellectual disability

is ameliorated by Kdm5^{UASp.C.Tag:HA,TurboID}

(Yheskel et al., 2023)

is ameliorated by Kdm5^{UASp.N.Tag:HA,TurboID}

(Yheskel et al., 2023)

model of syndromic intellectual disability

is exacerbated by pros¹⁷

(Hatch et al., 2021)

Kdm5^{UASp.C.Tag:HA,TurboID}

ameliorates intellectual disability

modeled by Kdm5¹⁴⁰

(Yheskel et al., 2023)

Kdm5^{UASp.N.Tag:HA,TurboID}

ameliorates intellectual disability

modeled by Kdm5¹⁴⁰

(Yheskel et al., 2023)

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

Kdm5^{UASp.C.Tag:HA,TurboID}

M{UASp-Kdm5.C.HA.TurboID}

Kdm5^{UASp.N.Tag:HA,TurboID}

M{UASp-Kdm5.N.HA.TurboID}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Kdm5^HMS05973

P{TRiP.HMS05973}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS05973}attP2

w¹¹¹⁸; P{GD14113}v42203

y¹ v¹; P{TRiP.HM05155}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.GLV21071}attP2/TM3, Sb¹

Kdm5^GL00612

P{TRiP.GL00612}

y¹ sc^* v¹ sev²¹; P{TRiP.GL00612}attP40

Kdm5^NIG.9088R

P{NIG.9088R}

P{NIG.9088R}1

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Kdm5¹⁴⁰

amorphic allele - molecular evidence

Delta2-3 transposase

Kdm5¹⁰⁴²⁴

P-element activity

cn¹ P{PZ}Kdm5¹⁰⁴²⁴/CyO; ry⁵⁰⁶

Kdm5^k06801

P-element activity

y^d2 w¹¹¹⁸ P{ey-FLP.N}2 P{5xglBS-lacZ.38-1}TPN1; P{lacW}Kdm5^k06801 P{neoFRT}40A/CyO y⁺

Kdm5^Q8

loss of function allele

ethyl methanesulfonate

Kdm5^Q19

loss of function allele

ethyl methanesulfonate

Kdm5^I1

loss of function allele

ethyl methanesulfonate

References (6)

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