Human Disease Model Report: cardiomyopathy, TNNI3-related

General Information

Name

cardiomyopathy, TNNI3-related

FlyBase ID

FBhh0000420

Disease Ontology Term

cardiomyopathy

Parent Disease

OMIM

Overview

This report describes fly models relevant to cardiomyopathies that are TNNI3-related. The human gene implicated in these diseases (TNNI3) encodes cardiac-type troponin I, a component of sarcomere thin filaments. TNNI3 is implicated in several forms of heart disease (see MIM:191044), including CMD1FF (FBhh0000166), CMD2A (FBhh0000165), CMH7 (FBhh0000415), and familial restrictive cardiomyopathy 1 (MIM:115210). Involvement of TNNI3 with hypertrophic cardiomyopathy is strongly supported by a large-scale WES analysis (Walsh, et al., 2016; pubmed:27532257).

A UAS construct of a tagged wild-type human Hsap\TNNI3 gene has been introduced into flies and has been made available; it has not been characterized.

There is one fly ortholog of TNNI3, wupA; Dmel\wupA is also orthologous to human genes TNNI1 and TNNI2, which are described as skeletal-type troponins. Multiple genetic reagents have been been generated for the wupA gene including classical loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis. Homozygous loss-of-function alleles are lethal in the embryonic stage. A well-characterized missense mutation that survives to adulthood exhibits multiple defects in heart function, indirect flight muscle hypercontraction, and other muscle defects. Genetic and physical interactions of Dmel\wupA have been described; see below and the wupA gene report.

[updated Apr. 2018 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: cardiomyopathy, TNNI3-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

The troponin complex is located on the thin filament of striated muscle and is composed of 3 component polypeptides: troponin I (TNNI1, MIM:191042; TNNI2, MIM:191043; and TNNI3, OMIM), troponin T (TNNT1, MIM:191041; and TNNT2, MIM:191045), and troponin C (TNNC1, MIM:191040; and TNNC2 MIM:191039). [From MIM:191044; 2016.02.02]

(OMIM, 2013-)

External links

Gene2Function (human gene): TNNI3
Gene Cards: TNNI3
MedlinePlus (condition): familial hypertrophic cardiomyopathy
MedlinePlus (condition): Familial dilated cardiomyopathy
MedlinePlus (gene): TNNI3
KEGG Disease Pathways: Dilated cardiomyopathy-Homo sapiens (human)
KEGG Disease Pathways: Hypertrophic cardiomyopathy (HCM)
MARRVEL (human gene): TNNI3
NCBI MedGen: Primary dilated cardiomyopathy (DCM)
NCBI MedGen: Primary familial hypertrophic cardiomyopathy (HCM)
NCBI (Entrez) gene: TNNI3; troponin I3, cardiac type

Disease synonyms

Related Diseases

Related human health report(s)

cardiomyopathy

cardiomyopathy, familial hypertrophic 7

cardiomyopathy, familial restrictive 1

dilated cardiomyopathy 1FF

dilated cardiomyopathy 2A

Ortholog Information

Human gene(s) in FlyBase

Hsap\TNNI3

Human gene (HGNC)

Symbol / Name

TNNI3; troponin I3, cardiac type

D. melanogaster ortholog (based on DIOPT)

Dmel\wupA

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 3 human to 1 Drosophila; additional human orthologs are TNNI1 and TNNI2. TNNI3 is described as cardiac-type I troponin; TNNI1 and TNNI2 are described as skeletal-type I troponins.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\wupA

Gene Snapshot

wings up A (wupA) encodes a cytoskeletal protein of the troponin complex of the muscle thin filament. It is involved in calcium-dependent regulation of muscle contraction, and in development of the embryonic heart, skeletal muscle and flight muscle It also contributes to non-muscle functions such as apico-basal polarity formation, nuclear division and maintenance of nuclear integrity. [Date last reviewed: 2019-03-21]

Molecular function (GO)

actin binding

Cellular component (GO)

Gene Groups / Pathways

TPNI

Comments on ortholog(s)

Ortholog of human TNNI1, TNNI2, and TNNI3 (1 Drosophila to 3 human). Dmel\wupA shares 31-34% identity and 50-55% 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 (45 groups)

wupA

protein-protein

Interacting group

Assay

References

wupA - Act79B

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Actn

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Adh

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Ald1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - aPKC

anti bait coimmunoprecipitation, western blot

(Casas-Tintó and Ferrús, 2019)

wupA - Argk1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - ATPsynB

experimental knowledge based

(Guruharsha et al., 2011)

wupA - ATPsynCF6

experimental knowledge based

(Guruharsha et al., 2011)

wupA - ATPsynF

experimental knowledge based

(Guruharsha et al., 2011)

wupA - ATPsynO

experimental knowledge based

(Guruharsha et al., 2011)

wupA - baz

anti bait coimmunoprecipitation, western blot

(Casas-Tintó and Ferrús, 2019)

wupA - CG7920

experimental knowledge based

(Guruharsha et al., 2011)

wupA - CG14207

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Cs1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Cyt-c1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Cyt-c-p

experimental knowledge based

(Guruharsha et al., 2011)

wupA - dlg1

anti bait coimmunoprecipitation, western blot

(Casas-Tintó and Ferrús, 2019)

wupA - fln

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Gdh

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Gpdh1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - GstS1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - icln

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Lasp

anti tag coimmunoprecipitation, peptide massfingerprinting

(Fernandes and Schöck, 2014)

wupA - mAcon1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Mdh2

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Mf

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Mhc

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Mlc1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Mlc2

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Mpcp1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - ND-PDSW

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Ogdh1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - orb2

anti tag coimmunoprecipitation, western blot

(Khan et al., 2015)

wupA - osk

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Hurd et al., 2016)

wupA - Prm

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Scp1

experimental knowledge based

(Guruharsha et al., 2011)

wupA - Sumo

anti bait coimmunoprecipitation, western blot

(Sahota et al., 2009)

wupA - Tm2

experimental knowledge based

(Guruharsha et al., 2011)

wupA - TpnC4

experimental knowledge based

(Guruharsha et al., 2011)

wupA - TpnC41C

experimental knowledge based

(Guruharsha et al., 2011)

wupA - TpnC47D

two hybrid

(Hu et al., 2017.6.13)

wupA - Tppl

experimental knowledge based

(Guruharsha et al., 2011)

wupA - up

experimental knowledge based

(Guruharsha et al., 2011)

RNA-protein

Interacting group

Assay

References

wupA - Rbfox1

anti tag coimmunoprecipitation, quantitative reverse transcription pcr

(Nikonova et al., 2022)

wupA - Sxl

electrophoretic mobility shift assay, autoradiography

(Banerjee and Singh, 2021)

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

wupA

Models Based on Experimental Evidence ( 3 )

Allele

Disease

Evidence

References

wupA^hdp-2

model of cardiomyopathy

CEA

(Gautam et al., 2015, Naimi et al., 2001)

model of dilated cardiomyopathy

CEA

(Abraham and Wolf, 2013, Lin et al., 2011, Wolf et al., 2006)

model of heart disease

CEA

(Choma et al., 2011)

wupA^JF02172

model of adenocarcinoma

CEA with l(2)gl^GD4047, Ras85D^V12.cUa.UAS

(Casas-Tintó et al., 2016)

wupA^f06492

model of adenocarcinoma

CEA

(Casas-Tintó et al., 2016)

CEA with N^int.U.UAS

(Casas-Tintó et al., 2016)

Modifiers Based on Experimental Evidence ( 2 )

Allele

Disease

Interaction

References

wupA^hdp-2

model of dilated cardiomyopathy

is ameliorated by SERCA^wt.tinC

(Abraham and Wolf, 2013)

wupA^JF02172

ameliorates adenocarcinoma

modeled by l(2)gl^GD4047, Ras85D^V12.cUa.UAS

(Casas-Tintó et al., 2016)

exacerbates cancer

modeled by Rbf^HMS03004

(Parkhitko et al., 2021)

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

Cardiovascular Diseases

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Hsap\TNNI3^UAS.Tag:HA

PBac{UAS-hTNNI3.HA}

y¹ w^*; PBac{UAS-hTNNI3.HA}VK00037

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

wupA^GD10595

P{GD10595}

w¹¹¹⁸; P{GD10595}v34196

wupA^JF02172

P{TRiP.JF02172}

y¹ v¹; P{TRiP.JF02172}attP2

wupA^RNAi.L9.UAS

P{UAS-wupA.L9.RNAi}

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

wupA^PL87

loss of function allele

Delta2-3 transposase

wupA^PG31

loss of function allele

Delta2-3 transposase

wupA⁵⁰⁵¹

loss of function allele

X ray

wupA^hdp-2

wupA¹³¹⁹³

loss of function allele

X ray

wupA^hdp-3

loss of function allele

ethyl methanesulfonate

wupA⁹⁹¹⁶

loss of function allele

X ray

wupA⁸³⁸⁴

loss of function allele

X ray

wupA²³⁴³⁷

loss of function allele

wupA^f06492

w¹¹¹⁸ PBac{WH}wupA^f06492

References (19)

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