Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism.

Détails

ID Serval
serval:BIB_8EC385998F6A
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism.
Périodique
American Journal of Human Genetics
Auteur(s)
Sass J.O., Mohr V., Olbrich H., Engelke U., Horvath J., Fliegauf M., Loges N.T., Schweitzer-Krantz S., Moebus R., Weiler P., Kispert A., Superti-Furga A., Wevers R.A., Omran H.
ISSN
0002-9297 (Print)
ISSN-L
0002-9297
Statut éditorial
Publié
Date de publication
2006
Volume
78
Numéro
3
Pages
401-409
Langue
anglais
Résumé
N-terminal acetylation of proteins is a widespread and highly conserved process. Aminoacylase 1 (ACY1; EC 3.5.14) is the most abundant of the aminoacylases, a class of enzymes involved in hydrolysis of N-acetylated proteins. Here, we present four children with genetic deficiency of ACY1. They were identified through organic acid analyses using gas chromatography-mass spectrometry, revealing increased urinary excretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, leucine, glycine, valine, and isoleucine. Nuclear magnetic resonance spectroscopy analysis of urine samples detected a distinct pattern of N-acetylated metabolites, consistent with ACY1 dysfunction. Functional analyses of patients' lymphoblasts demonstrated ACY1 deficiency. Mutation analysis uncovered recessive loss-of-function or missense ACY1 mutations in all four individuals affected. We conclude that ACY1 mutations in these children led to functional ACY1 deficiency and excretion of N-acetylated amino acids. Questions remain, however, as to the clinical significance of ACY1 deficiency. The ACY1-deficient individuals were ascertained through urine metabolic screening because of unspecific psychomotor delay (one subject), psychomotor delay with atrophy of the vermis and syringomyelia (one subject), marked muscular hypotonia (one subject), and follow-up for early treated biotinidase deficiency and normal clinical findings (one subject). Because ACY1 is evolutionarily conserved in fish, frog, mouse, and human and is expressed in the central nervous system (CNS) in human, a role in CNS function or development is conceivable but has yet to be demonstrated. Thus, at this point, we cannot state whether ACY1 deficiency has pathogenic significance with pleiotropic clinical expression or is simply a biochemical variant. Awareness of this new genetic entity may help both in delineating its clinical significance and in avoiding erroneous diagnoses.
Mots-clé
Acetylation, Amidohydrolases/deficiency, Amidohydrolases/genetics, Amino Acid Metabolism, Inborn Errors/genetics, Amino Acid Sequence, Amino Acids/metabolism, Amino Acids/urine, Animals, Blotting, Northern, Child, Conserved Sequence, Genes, Humans, Mice, Molecular Sequence Data, Mutation, Rats, Sequence Alignment
Pubmed
Web of science
Open Access
Oui
Création de la notice
14/03/2011 17:09
Dernière modification de la notice
08/05/2019 21:53
Données d'usage