Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo.
Alleles
Amino Acid Sequence
Anemia, Hemolytic, Congenital Nonspherocytic
/ genetics
Animals
Base Sequence
Carbohydrate Metabolism, Inborn Errors
/ genetics
Catalytic Domain
Child, Preschool
Dimerization
Disease Models, Animal
Drosophila
/ metabolism
Drosophila Proteins
/ genetics
Female
Fibroblasts
/ cytology
Humans
Mutation, Missense
Pedigree
Protein Stability
Sequence Alignment
Triose-Phosphate Isomerase
/ deficiency
Genomic engineering
Glycolytic enzymopathy
TPI deficiency
Triosephosphate isomerase
Journal
Biochimica et biophysica acta. Molecular basis of disease
ISSN: 1879-260X
Titre abrégé: Biochim Biophys Acta Mol Basis Dis
Pays: Netherlands
ID NLM: 101731730
Informations de publication
Date de publication:
01 09 2019
01 09 2019
Historique:
received:
23
02
2018
revised:
20
12
2018
accepted:
06
01
2019
pubmed:
11
5
2019
medline:
8
5
2020
entrez:
11
5
2019
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 31075491
pii: S0925-4439(19)30159-0
doi: 10.1016/j.bbadis.2019.05.002
pmc: PMC6659405
mid: NIHMS1529802
pii:
doi:
Substances chimiques
Drosophila Proteins
0
Triose-Phosphate Isomerase
EC 5.3.1.1
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2257-2266Subventions
Organisme : NIA NIH HHS
ID : R21 AG059385
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS095614
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM108073
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG059386
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM103369
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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