Back to Search
Start Over
Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo
- Source :
- Biochim Biophys Acta Mol Basis Dis
- Publication Year :
- 2019
- Publisher :
- Elsevier B.V., 2019.
-
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 TPIArg189Gln/TPIGlu104Asp 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.
- Subjects :
- 0301 basic medicine
Hemolytic anemia
TPI deficiency
Mutation, Missense
Isomerase
010402 general chemistry
medicine.disease_cause
Compound heterozygosity
01 natural sciences
Article
Triosephosphate isomerase
03 medical and health sciences
Catalytic Domain
parasitic diseases
medicine
Missense mutation
Animals
Drosophila Proteins
Humans
Amino Acid Sequence
Genomic engineering
Allele
Molecular Biology
Alleles
chemistry.chemical_classification
Glycolytic enzymopathy
Mutation
Base Sequence
Protein Stability
Anemia, Hemolytic, Congenital Nonspherocytic
Fibroblasts
medicine.disease
Molecular biology
0104 chemical sciences
Pedigree
Disease Models, Animal
030104 developmental biology
Enzyme
chemistry
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
Child, Preschool
Molecular Medicine
Drosophila
Female
Dimerization
Sequence Alignment
Carbohydrate Metabolism, Inborn Errors
Triose-Phosphate Isomerase
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Biochim Biophys Acta Mol Basis Dis
- Accession number :
- edsair.doi.dedup.....a35e84e19c12344ce82117ef9c39b253