Human Disease Model Report: cardiac dysfunction (postulated), CCR4-NOT complexv

General Information

Name

cardiac dysfunction (postulated), CCR4-NOT complexv

FlyBase ID

FBhh0001273

Disease Ontology Term

heart disease

Parent Disease

OMIM

Overview

This report describes a Drosophila model used to characterize the roles of components of the CCR4-NOT complex in the development of cardiac dysfunction. The CCR4-NOT complex contributes to regulation of RNA metabolism at all steps, including transcription, mRNA stability, and eventual degradation in the cytoplasm. See FBgg0000469 for information on the component genes of the Drosophila CCR4-NOT complex. This report concentrates on work done using Drosophila genes Not1, ortholog of human CNOT1, and Pop2, ortholog of human CNOT7 and CNOT8.

CNOT1 has been recently associated with a newly described disease, Vissers-Bodmer syndrome (see FBhh0001252). Heterozygous loss-of-function mutations are implicated in development of this disease. Multiple UAS constructs of the human Hsap\CNOT1 gene have been introduced into flies; most carry variants implicated in Vissers-Bodmer syndrome.

The role of CNOT3 in the development of cardiac dysfunction has been the subject of a previous study in Drosophila; see the human disease model report 'dilated cardiomyopathy (postulated), CNOT3-related' (FBhh0000739).

Using a heart-specific driver that acts throughout development, knockdown of either Dmel\Not1 or Dmel\Pop2 results in an array of adult cardiac phenotypes including cardiac dilation, reduced contractility, and a propensity for arrythmia; myofibrillar structural abnormalities are observed. In the case of Not1, the adult hearts are extremely fragile, which limits experimental manipulations. In the case of Pop2, initial experiments resulted in pupal lethality; animals survive to adulthood with a lower level of RNAi-effected knockdown, allowing assessment of adult cardiac phenotypes.

Phenotypes observed using Dmel\Rga (ortholog of human CNOT2), Dmel\Cnot4 (ortholog of human CNOT4) and Dmel\twin (ortholog of human CNOT6 and CNOT6L) suggest less critical roles in heart development for these genes.

[updated Oct. 2020 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: cardiac dysfunction (postulated), CCR4-NOT complexv

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

Two conserved catalytic functions are associated with the CCR4-NOT complex, deadenylation and ubiquitination (Collart and Panasenko, 2017; pubmed:28271483).

(FlyBase Curators, 2013-)

The CCR4-NOT complex is a multisubunit protein complex that is conserved in all eukaryotes and contributes to regulation of RNA metabolism at all steps, from synthesis to degradation in the cytoplasm (Collart, 2016; pubmed:26821858).

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): CNOT1
Gene2Function (human gene): CNOT7 CCR4-NOT transcription complex subunit 7
Gene2Function (human gene): CNOT8 CCR4-NOT transcription complex subunit 8
Gene Cards: CNOT1
Gene Cards: CNOT7 gene
Gene Cards: CNOT8 gene
Gene Cards: CNOT7 CCR4-NOT transcription complex subunit 7
Gene Cards: CNOT8 CCR4-NOT transcription complex subunit 8
MedlinePlus (gene): CNOT1
MARRVEL (human gene): CNOT8 CCR4-NOT transcription complex subunit 8
MARRVEL (human gene): CNOT1
MARRVEL (human gene): CNOT7 CCR4-NOT transcription complex subunit 7
NCBI (Entrez) gene: CNOT1; CCR4-NOT transcription complex subunit 1
NCBI (Entrez) gene: CNOT7 CCR4-NOT transcription complex subunit 7
NCBI (Entrez) gene: CNOT8 CCR4-NOT transcription complex subunit 8

Disease synonyms

cardiac arrythmia (postulated), CNOT1-related

Related Diseases

Related human health report(s)

cardiac arrhythmias

cardiac dysfunction (fly models overview)

dilated cardiomyopathy

dilated cardiomyopathy (postulated), CNOT3-related

Ortholog Information

Human gene(s) in FlyBase

Hsap\CNOT1

Human gene (HGNC)

Symbol / Name

CNOT1; CCR4-NOT transcription complex subunit 1

D. melanogaster ortholog (based on DIOPT)

Dmel\Not1

(DIOPT, 2013-)

Dmel\Pop2

(DIOPT, 2013-)

Comments on ortholog(s)

One to one: 1 human gene to 1 Drosophila gene.

Many to one: 2 human genes to 2 Drosophila gene.

Many to one: 2 human gene to 2 Drosophila gene.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (2)

Dmel\Not1

Gene Snapshot

Not1 (Not1) encodes a poly(A)-specific ribonuclease involved in translation inhibition and ovarian follicle cell development. [Date last reviewed: 2019-08-01]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

CCR4-NOT

Comments on ortholog(s)

High-scoring ortholog of human CNOT1 (1 Drosophila to 1 human). Dmel\Not1 shares 46% identity and 62% similarity with the human gene.

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\Pop2

Gene Snapshot

Pop2 (Pop2) encodes a poly(A)-specific ribonuclease involved in translation inhibition. [Date last reviewed: 2019-08-01]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human CNOT7 and CNOT8 (1 Drosophila to 2 human). Dmel\Pop2 shares 56-68% identity and 68-84% 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 (42 groups)

Not1

RNA-protein

Interacting group

Assay

References

Not1 - bel

clip-seq

(Kotov et al., 2020)

protein-protein

Interacting group

Assay

References

Not1 - Atx2

anti bait coimmunoprecipitation, western blot

(Lee et al., 2017)

Not1 - aub

anti tag coimmunoprecipitation, western blot

(Rojas-Ríos et al., 2017)

Not1 - bam

pull down, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot

(Sgromo et al., 2018)

Not1 - cu

anti bait coimmunoprecipitation, anti tag western blot

(Temme et al., 2010)

Not1 - cup

anti tag coimmunoprecipitation, anti tag western blot

(Igreja and Izaurralde, 2011)

Not1 - gw

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

(Huntzinger et al., 2013, Braun et al., 2011)

Not1 - Gyf

anti tag coimmunoprecipitation, anti tag western blot

(Ruscica et al., 2019)

Not1 - Helz

anti tag coimmunoprecipitation, anti tag western blot

(Hanet et al., 2019)

Not1 - Marf

colocalization, fluorescence microscopy, inferred by author

(Salgania et al., 2024)

Not1 - Marf1

anti tag coimmunoprecipitation, western blot

(Zhu et al., 2018)

Not1 - me31B

anti tag coimmunoprecipitation, western blot

(Lee et al., 2017)

Not1 - nanos

pull down, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot, western blot, colocalization, fluorescence microscopy, inferred by author

(Salgania et al., 2024, Arvola et al., 2020, Raisch et al., 2016)

Not1 - Not3

molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, western blot, anti tag western blot, colocalization, fluorescence microscopy, inferred by author, anti bait coimmunoprecipitation, Identification by mass spectrometry, experimental knowledge based

(Pekovic and Wahle, 2024, Salgania et al., 2024, Arvola et al., 2020, Bawankar et al., 2013, Guruharsha et al., 2011, Temme et al., 2010)

Not1 - Not10

anti tag coimmunoprecipitation, anti tag western blot

(Bawankar et al., 2013)

Not1 - Not11

pull down, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot

(Haugen et al., 2022, Bawankar et al., 2013)

Not1 - piwi

anti bait coimmunoprecipitation, western blot

(Kordyukova et al., 2020)

Not1 - Pop2

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, molecular sieving, molecular weight estimation by staining, colocalization, fluorescence microscopy, inferred by author, experimental knowledge based, Identification by mass spectrometry

(Pekovic and Wahle, 2024, Salgania et al., 2024, Bawankar et al., 2013, Petit et al., 2012, Guruharsha et al., 2011, Temme et al., 2010)

Not1 - Pos

anti tag coimmunoprecipitation, anti tag western blot

(Xia et al., 2022)

Not1 - pum

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

(Haugen et al., 2022, Arvola et al., 2020)

Not1 - Rcd-1

colocalization, fluorescence microscopy, inferred by author, anti tag coimmunoprecipitation, anti tag western blot, molecular sieving, molecular weight estimation by staining

(Pekovic and Wahle, 2024, Salgania et al., 2024, Xia et al., 2022, Bawankar et al., 2013)

Not1 - Rga

anti tag coimmunoprecipitation, anti tag western blot, colocalization, fluorescence microscopy, inferred by author, western blot, anti bait coimmunoprecipitation, Identification by mass spectrometry, molecular sieving, molecular weight estimation by staining, experimental knowledge based

(Pekovic and Wahle, 2024, Salgania et al., 2024, Arvola et al., 2020, Bawankar et al., 2013, Guruharsha et al., 2011, Temme et al., 2010)

Not1 - rictor

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Not1 - roq

colocalization, fluorescence microscopy, inferred by author, anti tag coimmunoprecipitation, anti tag western blot

(Salgania et al., 2024, Sgromo et al., 2017)

Not1 - RpL10Ab

pull down, western blot

(Antic et al., 2015)

Not1 - smg

two hybrid, tandem affinity purification, Identification by mass spectrometry

(Pekovic et al., 2023, Semotok et al., 2005)

Not1 - thoc5

anti bait coimmunoprecipitation, western blot

(Kordyukova et al., 2020)

Not1 - twin

anti bait coimmunoprecipitation, western blot, experimental knowledge based, molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, Identification by mass spectrometry, anti tag western blot

(Pekovic and Wahle, 2024, Kordyukova et al., 2020, Morgunova et al., 2015, Bawankar et al., 2013, Joly et al., 2013, Guruharsha et al., 2011, Temme et al., 2010)

Pop2

protein-protein

Interacting group

Assay

References

Pop2 - AGO1

anti bait coimmunoprecipitation, western blot

(Iwasaki et al., 2009)

Pop2 - cu

anti tag coimmunoprecipitation, western blot

(Temme et al., 2010)

Pop2 - cup

anti tag coimmunoprecipitation, anti tag western blot

(Igreja and Izaurralde, 2011)

Pop2 - Gyf

anti tag coimmunoprecipitation, anti tag western blot

(Ruscica et al., 2019)

Pop2 - Not1

(Pekovic and Wahle, 2024, Salgania et al., 2024, Bawankar et al., 2013, Petit et al., 2012, Guruharsha et al., 2011, Temme et al., 2010)

Pop2 - Not3

molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot, colocalization, fluorescence microscopy, inferred by author

(Pekovic and Wahle, 2024, Salgania et al., 2024, Zekri et al., 2009)

Pop2 - Patr-1

anti tag coimmunoprecipitation, anti tag western blot

(Haas et al., 2010)

Pop2 - pum

pull down, autoradiography, anti tag western blot

(Weidmann et al., 2014, Kadyrova et al., 2007)

Pop2 - Rcd-1

colocalization, fluorescence microscopy, inferred by author, molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot

(Pekovic and Wahle, 2024, Salgania et al., 2024, Bawankar et al., 2013)

Pop2 - Rga

anti tag coimmunoprecipitation, anti tag western blot, molecular sieving, molecular weight estimation by staining

(Pekovic and Wahle, 2024, Haugen et al., 2022)

Pop2 - roq

anti tag coimmunoprecipitation, anti tag western blot

(Sgromo et al., 2017)

Pop2 - smg

anti tag coimmunoprecipitation, western blot

(Semotok et al., 2005)

Pop2 - Tob

anti tag coimmunoprecipitation, anti tag western blot, two hybrid

(Hu et al., 2017.6.13, White-Grindley et al., 2014)

Pop2 - twin

anti tag coimmunoprecipitation, anti tag western blot, western blot, colocalization, fluorescence microscopy, inferred by author, ion exchange chromatography, molecular sieving, molecular weight estimation by staining, experimental knowledge based

(Pekovic and Wahle, 2024, Salgania et al., 2024, Fu et al., 2015, Bawankar et al., 2013, Joly et al., 2013, Petit et al., 2012, Guruharsha et al., 2011, Temme et al., 2010, Temme et al., 2004)

RNA-protein

Interacting group

Assay

References

Pop2 - nanos

pull down, western blot, Identification by mass spectrometry

(Götze et al., 2017, Jeske et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (18 alleles)

Hsap\CNOT1

Models Based on Experimental Evidence ( 8 )

Allele

Disease

Evidence

References

Hsap\CNOT1^Q33X.UAS

model of Vissers-Bodmer syndrome

CEA

(Vissers et al., 2020)

Hsap\CNOT1^Y396X.UAS

model of Vissers-Bodmer syndrome

CEA

(Vissers et al., 2020)

Hsap\CNOT1^R535C.UAS

model of Vissers-Bodmer syndrome

CEA

(Vissers et al., 2020)

Hsap\CNOT1^Q642E.UAS

model of Vissers-Bodmer syndrome

CEA

(Vissers et al., 2020)

Hsap\CNOT1^R900C.UAS

model of Vissers-Bodmer syndrome

CEA

(Vissers et al., 2020)

Hsap\CNOT1^L1148P.UAS

model of Vissers-Bodmer syndrome

CEA

(Vissers et al., 2020)

Hsap\CNOT1^K1241R.UAS

model of Vissers-Bodmer syndrome

CEA

(Vissers et al., 2020)

Hsap\CNOT1^N2216S.UAS

model of Vissers-Bodmer syndrome

CEA

(Vissers et al., 2020)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

Hsap\CNOT1^UAS.cVa

ameliorates Vissers-Bodmer syndrome

modeled by Not1^GD4070

(Vissers et al., 2020)

modeled by Not1^KK100090

(Vissers et al., 2020)

Not1

Models Based on Experimental Evidence ( 3 )

Allele

Disease

Evidence

References

Not1^GD4070

model of heart disease

CEA

(Elmén et al., 2020)

model of Vissers-Bodmer syndrome

CEA

(Vissers et al., 2020)

Not1^GD9640

model of cancer

CEA with Delta^UAS.cDa

(Vicente et al., 2018)

Not1^KK100090

model of Vissers-Bodmer syndrome

CEA

(Vissers et al., 2020)

Modifiers Based on Experimental Evidence ( 5 )

Allele

Disease

Interaction

References

Not1^HMS00526

exacerbates tauopathy

modeled by Hsap\MAPT^UAS.cWa

(Feuillette et al., 2020)

exacerbates cancer

modeled by Rbf^HMS03004

(Parkhitko et al., 2021)

Not1^JF01135

exacerbates tauopathy

modeled by Hsap\MAPT^UAS.cWa

(Feuillette et al., 2020)

Not1^GD4070

model of Vissers-Bodmer syndrome

is ameliorated by E(z)^RNAi.UAS.cUa

(Vissers et al., 2020)

is ameliorated by Hsap\CNOT1^UAS.cVa

(Vissers et al., 2020)

is exacerbated by Prosap^GD10101

(Vissers et al., 2020)

is exacerbated by Prosap^KK101537

(Vissers et al., 2020)

is exacerbated by ash1^KK100243

(Vissers et al., 2020)

is ameliorated by esc^RNAi.UAS.cUa

(Vissers et al., 2020)

is exacerbated by mnb^GL00104

(Vissers et al., 2020)

is exacerbated by mnb^KK102642

(Vissers et al., 2020)

is exacerbated by skd^HMS01305

(Vissers et al., 2020)

is ameliorated by skd^UAS.cJa

(Vissers et al., 2020)

is exacerbated by skd^VSH330726

(Vissers et al., 2020)

is ameliorated by E(z)^RNAi.UAS.cUa

(Vissers et al., 2020)

Not1^KK100090

model of Vissers-Bodmer syndrome

is ameliorated by Hsap\CNOT1^UAS.cVa

(Vissers et al., 2020)

Not1^JF03096

exacerbates tauopathy

modeled by Hsap\MAPT^UAS.cWa

(Feuillette et al., 2020)

Pop2

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

Pop2^HM05235

model of heart disease

CEA

(Elmén et al., 2020)

Pop2^GD12804

model of cancer

CEA with Delta^UAS.cDa

(Vicente et al., 2018)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

Pop2^DG14804

ameliorates oculopharyngeal muscular dystrophy

modeled by Hsap\PABPN1^17ala.Act88F

(Chartier 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\CNOT1^L1148P.UAS

P{UAS-hCNOT1.L1148P}

Hsap\CNOT1^K1241R.UAS

P{UAS-hCNOT1.K1241R}

Hsap\CNOT1^F1428S.UAS

P{UAS-hCNOT1.F1428S}

Hsap\CNOT1^R1478C.UAS

P{UAS-hCNOT1.R1478C}

Hsap\CNOT1^N2216S.UAS

P{UAS-hCNOT1.N2216S}

Hsap\CNOT1^{L2102S.fs4.UAS}

P{UAS-hCNOT1.L2102S.fs4}

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

w¹¹¹⁸; P{GD12804}v28396/CyO

Pop2^HM05235

P{TRiP.HM05235}

y¹ sc^* v¹ sev²¹; P{TRiP.HM05235}attP2

y¹ v¹; P{TRiP.HMJ21614}attP40/CyO

w¹¹¹⁸; P{GD9640}v45463/CyO

y¹ v¹; P{TRiP.JF03096}attP2

Not1^JF01135

P{TRiP.JF01135}

y¹ v¹; P{TRiP.JF01135}attP2

Not1^HMS00526

P{TRiP.HMS00526}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00526}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Pop2^DG14804

References (3)

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