Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo

Bartholomew P. Roland, Kristen R. Richards, Stacy L. Hrizo, Samantha Eicher, Zackery J. Barile, Tien Chien Chang, Grace Savon, Paola Bianchi, Elisa Fermo, Bianca Maria Ricerca, Luca Tortorolo, Jerry Vockley, Andrew P. VanDemark, Michael J. Palladino

Research output: Contribution to journalArticle

Abstract

Mutations in the gene triosephosphate isomerase (TPI) lead to a severe multisystem condition that is characterized by hemolytic anemia, a weakened immune system, and significant neurologic symptoms such as seizures, distal neuropathy, and intellectual disability. No effective therapy is available. Here we report a compound heterozygous patient with a novel TPI pathogenic variant (NM_000365.5:c.569G>A:p.(Arg189Gln)) in combination with the common (NM_000365.5:c.315G>C:p.(Glu104Asp)) allele. We characterized the novel variant by mutating the homologous Arg in Drosophila using a genomic engineering system, demonstrating that missense mutations at this position cause a strong loss of function. Compound heterozygote animals were generated and exhibit motor behavioural deficits and markedly reduced protein levels. Furthermore, examinations of the TPI Arg189Gln /TPI Glu104Asp patient fibroblasts confirmed the reduction of TPI levels, suggesting that Arg189Gln may also affect the stability of the protein. The Arg189 residue participates in two salt bridges on the backside of the TPI enzyme dimer, and we reveal that a mutation at this position alters the coordination of the substrate-binding site and important catalytic residues. Collectively, these data reveal a new human pathogenic variant associated with TPI deficiency, identify the Arg189 salt bridge as critical for organizing the catalytic site of the TPI enzyme, and demonstrates that reduced TPI levels are associated with human TPI deficiency. These findings advance our understanding of the molecular pathogenesis of the disease, and suggest new therapeutic avenues for pre-clinical trials.

Original languageEnglish
Pages (from-to)2257-2266
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1865
Issue number9
DOIs
Publication statusPublished - Jan 1 2019

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Triose-Phosphate Isomerase
Neurologic Manifestations
Catalytic Domain
Enzymes
Salts
Mutation
Protein Stability
Hemolytic Anemia
Missense Mutation
Heterozygote
Intellectual Disability
Drosophila
Immune System
Seizures
Fibroblasts
Alleles
Binding Sites
Clinical Trials

Keywords

  • Genomic engineering
  • Glycolytic enzymopathy
  • TPI deficiency
  • Triosephosphate isomerase

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo. / Roland, Bartholomew P.; Richards, Kristen R.; Hrizo, Stacy L.; Eicher, Samantha; Barile, Zackery J.; Chang, Tien Chien; Savon, Grace; Bianchi, Paola; Fermo, Elisa; Ricerca, Bianca Maria; Tortorolo, Luca; Vockley, Jerry; VanDemark, Andrew P.; Palladino, Michael J.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1865, No. 9, 01.01.2019, p. 2257-2266.

Research output: Contribution to journalArticle

Roland, Bartholomew P. ; Richards, Kristen R. ; Hrizo, Stacy L. ; Eicher, Samantha ; Barile, Zackery J. ; Chang, Tien Chien ; Savon, Grace ; Bianchi, Paola ; Fermo, Elisa ; Ricerca, Bianca Maria ; Tortorolo, Luca ; Vockley, Jerry ; VanDemark, Andrew P. ; Palladino, Michael J. / Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2019 ; Vol. 1865, No. 9. pp. 2257-2266.
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abstract = "Mutations in the gene triosephosphate isomerase (TPI) lead to a severe multisystem condition that is characterized by hemolytic anemia, a weakened immune system, and significant neurologic symptoms such as seizures, distal neuropathy, and intellectual disability. No effective therapy is available. Here we report a compound heterozygous patient with a novel TPI pathogenic variant (NM_000365.5:c.569G>A:p.(Arg189Gln)) in combination with the common (NM_000365.5:c.315G>C:p.(Glu104Asp)) allele. We characterized the novel variant by mutating the homologous Arg in Drosophila using a genomic engineering system, demonstrating that missense mutations at this position cause a strong loss of function. Compound heterozygote animals were generated and exhibit motor behavioural deficits and markedly reduced protein levels. Furthermore, examinations of the TPI Arg189Gln /TPI Glu104Asp patient fibroblasts confirmed the reduction of TPI levels, suggesting that Arg189Gln may also affect the stability of the protein. The Arg189 residue participates in two salt bridges on the backside of the TPI enzyme dimer, and we reveal that a mutation at this position alters the coordination of the substrate-binding site and important catalytic residues. Collectively, these data reveal a new human pathogenic variant associated with TPI deficiency, identify the Arg189 salt bridge as critical for organizing the catalytic site of the TPI enzyme, and demonstrates that reduced TPI levels are associated with human TPI deficiency. These findings advance our understanding of the molecular pathogenesis of the disease, and suggest new therapeutic avenues for pre-clinical trials.",
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T1 - Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo

AU - Roland, Bartholomew P.

AU - Richards, Kristen R.

AU - Hrizo, Stacy L.

AU - Eicher, Samantha

AU - Barile, Zackery J.

AU - Chang, Tien Chien

AU - Savon, Grace

AU - Bianchi, Paola

AU - Fermo, Elisa

AU - Ricerca, Bianca Maria

AU - Tortorolo, Luca

AU - Vockley, Jerry

AU - VanDemark, Andrew P.

AU - Palladino, Michael J.

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N2 - Mutations in the gene triosephosphate isomerase (TPI) lead to a severe multisystem condition that is characterized by hemolytic anemia, a weakened immune system, and significant neurologic symptoms such as seizures, distal neuropathy, and intellectual disability. No effective therapy is available. Here we report a compound heterozygous patient with a novel TPI pathogenic variant (NM_000365.5:c.569G>A:p.(Arg189Gln)) in combination with the common (NM_000365.5:c.315G>C:p.(Glu104Asp)) allele. We characterized the novel variant by mutating the homologous Arg in Drosophila using a genomic engineering system, demonstrating that missense mutations at this position cause a strong loss of function. Compound heterozygote animals were generated and exhibit motor behavioural deficits and markedly reduced protein levels. Furthermore, examinations of the TPI Arg189Gln /TPI Glu104Asp patient fibroblasts confirmed the reduction of TPI levels, suggesting that Arg189Gln may also affect the stability of the protein. The Arg189 residue participates in two salt bridges on the backside of the TPI enzyme dimer, and we reveal that a mutation at this position alters the coordination of the substrate-binding site and important catalytic residues. Collectively, these data reveal a new human pathogenic variant associated with TPI deficiency, identify the Arg189 salt bridge as critical for organizing the catalytic site of the TPI enzyme, and demonstrates that reduced TPI levels are associated with human TPI deficiency. These findings advance our understanding of the molecular pathogenesis of the disease, and suggest new therapeutic avenues for pre-clinical trials.

AB - Mutations in the gene triosephosphate isomerase (TPI) lead to a severe multisystem condition that is characterized by hemolytic anemia, a weakened immune system, and significant neurologic symptoms such as seizures, distal neuropathy, and intellectual disability. No effective therapy is available. Here we report a compound heterozygous patient with a novel TPI pathogenic variant (NM_000365.5:c.569G>A:p.(Arg189Gln)) in combination with the common (NM_000365.5:c.315G>C:p.(Glu104Asp)) allele. We characterized the novel variant by mutating the homologous Arg in Drosophila using a genomic engineering system, demonstrating that missense mutations at this position cause a strong loss of function. Compound heterozygote animals were generated and exhibit motor behavioural deficits and markedly reduced protein levels. Furthermore, examinations of the TPI Arg189Gln /TPI Glu104Asp patient fibroblasts confirmed the reduction of TPI levels, suggesting that Arg189Gln may also affect the stability of the protein. The Arg189 residue participates in two salt bridges on the backside of the TPI enzyme dimer, and we reveal that a mutation at this position alters the coordination of the substrate-binding site and important catalytic residues. Collectively, these data reveal a new human pathogenic variant associated with TPI deficiency, identify the Arg189 salt bridge as critical for organizing the catalytic site of the TPI enzyme, and demonstrates that reduced TPI levels are associated with human TPI deficiency. These findings advance our understanding of the molecular pathogenesis of the disease, and suggest new therapeutic avenues for pre-clinical trials.

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