Human Disease Model Report: triosephosphate isomerase deficiency

General Information

Name

triosephosphate isomerase deficiency

FlyBase ID

FBhh0000489

Disease Ontology Term

triosephosphate isomerase deficiency

Parent Disease

OMIM

TRIOSEPHOSPHATE ISOMERASE DEFICIENCY; TPID

Overview

Triosephosphate isomerase deficiency (TPID) is a glucose metabolism disorder falling into the category of disorders described as glycolytic enzymopathies; TPID exhibits autosomal recessive inheritance. It is unique among the glycolytic enzyme defects, most of which manifest clinically as chronic hemolytic anemias, since it is also associated with progressive and severe neurological dysfunction. The human gene implicated in this disease is triosephosphate isomerase (TPI1), which catalyzes the isomerization between dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. There is a single Drosophila ortholog, Dmel\Tpi, for which amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

The fly gene has been replaced in situ with a wild-type human Hsap\TPI1 gene (with modified codon usage) and with a human variant implicated in TPID. Heterologous rescue (functional complementation) has been demonstrated. Variant(s) implicated in human disease tested (as transgenic human gene, TPI1): the I170V (I208V) variant form of the human gene has been introduced into flies.

Amorphic mutations in the Dmel\Tpi gene are recessive lethals. Animals homozygous or hemizygous for different missense mutations show phenotypes including reduced longevity, progressive locomotor deficiency, induced paralytic phenotypes, and neural degeneration; phenotypes become worse under conditions of oxidative stress; at a cellular level, synaptic vesicle dysfunction is observed. A particular human variant, TPI1:Arg227Gln (referred to in FBrf0242891 as Arg190Gln), was introduced to Drosophila via multiple analogous mutations (Arg changed to Ala, Lys, Ser, and Leu) in the fly gene, and all variants other than Arg187Lys in Dmel\Tpi show defects.

[updated November 2019 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: triosephosphate isomerase deficiency

OMIM report

[TRIOSEPHOSPHATE ISOMERASE DEFICIENCY; TPID](https://omim.org/entry/615512)

Human gene(s) implicated

[TRIOSEPHOSPHATE ISOMERASE 1; TPI1](https://omim.org/entry/190450)

Symptoms and phenotype

Many glycolytic enzymopathies have been described that manifest clinically as chronic hemolytic anemia. Triosephosphate isomerase (TPI) deficiency, is unique among the glycolytic enzyme defects since it is associated with progressive neurological dysfunction and frequently with childhood death. (Orosz et al., 2006; PMID: 17424909)

(FlyBase Curators, 2013-)

Triosephosphate isomerase deficiency is characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction beginning in early childhood. The neurologic syndrome is variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Many patients die from respiratory failure in childhood. (summary by Fermo et al., 2010; pubmed:20374271) [from MIM:615512; 2017.01.30]

(OMIM, 2013-)

Genetics

Triosephosphate isomerase deficiency (TPID) is caused by homozygous or compound heterozygous mutation in the TPI1 gene (autosomal recessive). [from MIM:615512; 2017.01.30]

(OMIM, 2013-)

Cellular phenotype and pathology

Intracellular accumulation of dihydroxyacetone phosphate (DHAP) is observed, particularly in red blood cells. (summary by Fermo et al., 2010; pubmed:20374271) [from MIM:615512; 2017.01.30]

(OMIM, 2013-)

Molecular information

The TPI1 gene encodes triosephosphate isomerase 1, a homodimeric enzyme that catalyzes the interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate during glycolysis and gluconeogenesis (summary by Chang et al., 1993; pubmed:8503454). [from MIM:190450; 2017.01.30]

(OMIM, 2013-)

External links

Gene2Function (human gene): TPI1
Gene Cards: TPI1
MedlinePlus (condition): triosephosphate isomerase deficiency
MedlinePlus (gene): TPI1
MARRVEL (human gene): TPI1
NCBI MedGen: Triosephosphate isomerase deficiency (TPID)
NCBI (Entrez) gene: TPI1; triosephosphate isomerase 1
National Organization for Rare Disorders: Triosephosphate Isomerase Deficiency

Disease synonyms

hemolytic anemia due to triosephosphate isomerase deficiency

Search term: glycolytic enzymopathy

TPID

TPI deficiency

triose phosphate-isomerase deficiency

Related Diseases

Related human health report(s)

Ortholog Information

Human gene(s) in FlyBase

Hsap\TPI1

Human gene (HGNC)

Symbol / Name

TPI1; triosephosphate isomerase 1

D. melanogaster ortholog (based on DIOPT)

Dmel\Tpi

(DIOPT, 2013-)

Comments on ortholog(s)

One to one (1 human to 1 Drosophila).

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Tpi

Gene Snapshot

Triose phosphate isomerase (Tpi) encodes a soluble metabolic protein dimer that functions in glycolysis catalyzing the isomerization between dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which is essential for efficient ATP production. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human TPI1 (1 Drosophila to 1 human). Dmel\Tpi shares 63% identity and 74% similarity with human TPI1.

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 (11 groups)

Tpi

protein-protein

Interacting group

Assay

References

Tpi

anti tag coimmunoprecipitation, western blot

(Roland et al., 2016)

Tpi - AhcyL1

experimental knowledge based

(Guruharsha et al., 2011)

Tpi - Antdh

experimental knowledge based

(Guruharsha et al., 2011)

Tpi - grsm

experimental knowledge based

(Guruharsha et al., 2011)

Tpi - Hsp70Aa

anti bait coimmunoprecipitation, western blot

(Hrizo and Palladino, 2010)

Tpi - Hsp83

anti bait coimmunoprecipitation, western blot

(Hrizo and Palladino, 2010)

Tpi - Mapmodulin

experimental knowledge based

(Guruharsha et al., 2011)

Tpi - Obp19d

experimental knowledge based

(Guruharsha et al., 2011)

Tpi - Pez

experimental knowledge based

(Guruharsha et al., 2011)

Tpi - pr

experimental knowledge based

(Guruharsha et al., 2011)

Tpi - Syx6

experimental knowledge based

(Guruharsha et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (20 alleles)

Tpi

Models Based on Experimental Evidence ( 18 )

Allele

Disease

Evidence

References

Tpi^wstd-1

model of triosephosphate isomerase deficiency

CEA

(Stone et al., 2023, Gnerer et al., 2006)

Tpi^sgk-js10

model of triosephosphate isomerase deficiency

CEA with Tpi^hTPI.I170V

(Roland et al., 2015)

CEA with Tpi^sgk-js10

(Roland et al., 2016)

CEA with Tpi^hTPI.M82T, Hsap\TPI1^M82T.Tpi

(Roland et al., 2016)

CEA with Tpi^M80T

(Roland et al., 2019)

DOES NOT model triosephosphate isomerase deficiency

CEA with Tpi^hTPI.WT, Hsap\TPI1^Tpi.WT

(Roland et al., 2016)

Tpi^sgk-1

model of triosephosphate isomerase deficiency

CEA

(Hrizo et al., 2013, Roland et al., 2013, Celotto et al., 2006)

model of neurodegenerative disease

CEA

(Celotto et al., 2006)

Tpi^GD10138

DOES NOT model triosephosphate isomerase deficiency

CEA

(Roland et al., 2016)

Tpi^K11M

model of triosephosphate isomerase deficiency

CEA with Tpi^T74R

(Roland et al., 2016)

CEA with Tpi^G75E

(Roland et al., 2016)

CEA with Tpi^T74R.G75E

(Roland et al., 2016)

Tpi^M80T

model of triosephosphate isomerase deficiency

CEA with Tpi^sgk-js10

(Roland et al., 2019, Roland et al., 2016)

CEA with Tpi^R188A

(Roland et al., 2019)

CEA with Tpi^R188L

(Roland et al., 2019)

CEA with Tpi^R188S

(Roland et al., 2019)

CEA

(Fogle et al., 2019)

Tpi^hTPI.WT

DOES NOT model triosephosphate isomerase deficiency

CEA with Tpi^sgk-js10, Hsap\TPI1^Tpi.WT

(Roland et al., 2016)

Tpi^hTPI.I170V

model of triosephosphate isomerase deficiency

CEA with Tpi^sgk-js10

(Roland et al., 2015)

Tpi^T74R

model of triosephosphate isomerase deficiency

CEA

(Roland et al., 2016)

CEA with Tpi^K11M

(Roland et al., 2016)

CEA with Tpi^T73R-CFP

(Roland et al., 2016)

Tpi^G75E

model of triosephosphate isomerase deficiency

CEA

(Roland et al., 2016)

CEA with Tpi^K11M

(Roland et al., 2016)

CEA with Tpi^G74E-CFP

(Roland et al., 2016)

Tpi^T74R.G75E

model of triosephosphate isomerase deficiency

CEA

(Roland et al., 2016)

CEA with Tpi^K11M

(Roland et al., 2016)

CEA with Tpi^{T73R.G74E-CFP}

(Roland et al., 2016)

Tpi^T73R-CFP

model of triosephosphate isomerase deficiency

CEA with Tpi^T74R

(Roland et al., 2016)

Tpi^G74E-CFP

model of triosephosphate isomerase deficiency

CEA with Tpi^G74E-CFP

(Roland et al., 2016)

Tpi^{T73R.G74E-CFP}

model of triosephosphate isomerase deficiency

CEA with Tpi^{T73R.G74E-CFP}

(Roland et al., 2016)

Tpi^hTPI.M82T

model of triosephosphate isomerase deficiency

CEA with Tpi^sgk-js10, Hsap\TPI1^M82T.Tpi

(Roland et al., 2016)

Tpi^R188A

model of triosephosphate isomerase deficiency

CEA with Tpi^M80T

(Roland et al., 2019)

Tpi^R188L

model of triosephosphate isomerase deficiency

CEA with Tpi^M80T

(Roland et al., 2019)

Tpi^R188S

model of triosephosphate isomerase deficiency

CEA with Tpi^M80T

(Roland et al., 2019)

Modifiers Based on Experimental Evidence ( 3 )

Allele

Disease

Interaction

References

Tpi^sgk-1

model of triosephosphate isomerase deficiency

is ameliorated by Tpi^K11M

(Roland et al., 2013)

Tpi^GD10138

exacerbates Parkinson's disease

modeled by Hsap\SNCA^UAS.cFa

(Vicente Miranda et al., 2017)

exacerbates Huntington's disease

modeled by Hsap\HTT^Q93.ex1.UAS

(Vicente Miranda et al., 2016)

Tpi^K11M

ameliorates triosephosphate isomerase deficiency

modeled by Tpi^sgk-1

(Roland et al., 2013)

Hsap\TPI1

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

Hsap\TPI1^Tpi.WT

DOES NOT model triosephosphate isomerase deficiency

CEA with Tpi^hTPI.WT, Tpi^sgk-js10

(Roland et al., 2016)

Hsap\TPI1^M82T.Tpi

model of triosephosphate isomerase deficiency

CEA with Tpi^hTPI.M82T, Tpi^sgk-js10

(Roland et al., 2016)

Modifiers Based on Experimental Evidence ( 0 )

Allele

Disease

Interaction

References

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

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Tpi^HMJ22470

P{TRiP.HMJ22470}

y¹ v¹; P{TRiP.HMJ22470}attP40/CyO

Tpi^GD10138

P{GD10138}

w¹¹¹⁸; P{GD10138}v25643

Tpi^JF02074

P{TRiP.JF02074}

y¹ v¹; P{TRiP.JF02074}attP2

y¹ v¹; P{TRiP.HMC03401}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

phiC31 integrase

phiC31 integrase

phiC31 integrase

Delta2-3 transposase

ethyl methanesulfonate

phiC31 integrase

phiC31 integrase

amorphic allele - molecular evidence

ends-out gene targeting

Tpi^hTPI.WT

loss of function allele

phiC31 integrase

Tpi^hTPI.I170V

loss of function allele

phiC31 integrase

phiC31 integrase

phiC31 integrase

phiC31 integrase

phiC31 integrase

phiC31 integrase

phiC31 integrase

phiC31 integrase

References (18)

Report Sections

Open Close