Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.

Phosphoglycerate kinase (PGK) catalyzes an important ATP-generating step in glycolysis. PGK1 deficiency is an uncommon X-linked inherited disorder, generally characterized by various combinations of non-spherocytic hemolytic anemia, neurological dysfunctions, and myopathies. Patients rarely exhibit...

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Autores principales:	Laurent R Chiarelli, Simone M Morera, Paola Bianchi, Elisa Fermo, Alberto Zanella, Alessandro Galizzi, Giovanna Valentini
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d93d0e0dc7be47b7a472f97bea7ebc60
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spelling	oai:doaj.org-article:d93d0e0dc7be47b7a472f97bea7ebc602021-11-18T07:28:17ZMolecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.1932-620310.1371/journal.pone.0032065https://doaj.org/article/d93d0e0dc7be47b7a472f97bea7ebc602012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22348148/?tool=EBIhttps://doaj.org/toc/1932-6203Phosphoglycerate kinase (PGK) catalyzes an important ATP-generating step in glycolysis. PGK1 deficiency is an uncommon X-linked inherited disorder, generally characterized by various combinations of non-spherocytic hemolytic anemia, neurological dysfunctions, and myopathies. Patients rarely exhibit all three clinical features. To provide a molecular framework to the different pathological manifestations, all known mutations were reviewed and 16 mutant enzymes, obtained as recombinant forms, were functionally and structurally characterized. Most mutations heavily affect thermal stability and to a different extent catalytic efficiency, in line with the remarkably low PGK activity clinically observed in the patients. Mutations grossly impairing protein stability, but moderately affecting kinetic properties (p.I47N, p.L89P, p.C316R, p.S320N, and p.A354P) present the most homogeneous correlation with the clinical phenotype. Patients carrying these mutations display hemolytic anemia and neurological disorders, and,except for p.A354P variant, no myopaty. Variants highly perturbed in both catalytic efficiency (p.G158V, p.D164V, p.K191del, D285V, p.D315N, and p.T378P) and heat stability (all, but p.T378P) result to be mainly associated with myopathy alone. Finally, mutations faintly affecting molecular properties (p.R206P, p.E252A, p.I253T, p.V266M, and p.D268N) correlate with a wide spectrum of clinical symptoms. These are the first studies that correlate the clinical symptoms with the molecular properties of the mutant enzymes. All findings indicate that the different clinical manifestations associated with PGK1 deficiency chiefly depend on the distinctive type of perturbations caused by mutations in the PGK1 gene, highlighting the need for determination of the molecular properties of PGK variants to assist in prognosis and genetic counseling. However, the clinical symptoms can not be understood only on the bases of molecular properties of the mutant enzyme. Different (environmental, metabolic, genetic and/or epigenetic) intervening factors can contribute toward the expression of PGK deficient clinical phenotypes.Laurent R ChiarelliSimone M MoreraPaola BianchiElisa FermoAlberto ZanellaAlessandro GalizziGiovanna ValentiniPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 2, p e32065 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Laurent R Chiarelli Simone M Morera Paola Bianchi Elisa Fermo Alberto Zanella Alessandro Galizzi Giovanna Valentini Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
description	Phosphoglycerate kinase (PGK) catalyzes an important ATP-generating step in glycolysis. PGK1 deficiency is an uncommon X-linked inherited disorder, generally characterized by various combinations of non-spherocytic hemolytic anemia, neurological dysfunctions, and myopathies. Patients rarely exhibit all three clinical features. To provide a molecular framework to the different pathological manifestations, all known mutations were reviewed and 16 mutant enzymes, obtained as recombinant forms, were functionally and structurally characterized. Most mutations heavily affect thermal stability and to a different extent catalytic efficiency, in line with the remarkably low PGK activity clinically observed in the patients. Mutations grossly impairing protein stability, but moderately affecting kinetic properties (p.I47N, p.L89P, p.C316R, p.S320N, and p.A354P) present the most homogeneous correlation with the clinical phenotype. Patients carrying these mutations display hemolytic anemia and neurological disorders, and,except for p.A354P variant, no myopaty. Variants highly perturbed in both catalytic efficiency (p.G158V, p.D164V, p.K191del, D285V, p.D315N, and p.T378P) and heat stability (all, but p.T378P) result to be mainly associated with myopathy alone. Finally, mutations faintly affecting molecular properties (p.R206P, p.E252A, p.I253T, p.V266M, and p.D268N) correlate with a wide spectrum of clinical symptoms. These are the first studies that correlate the clinical symptoms with the molecular properties of the mutant enzymes. All findings indicate that the different clinical manifestations associated with PGK1 deficiency chiefly depend on the distinctive type of perturbations caused by mutations in the PGK1 gene, highlighting the need for determination of the molecular properties of PGK variants to assist in prognosis and genetic counseling. However, the clinical symptoms can not be understood only on the bases of molecular properties of the mutant enzyme. Different (environmental, metabolic, genetic and/or epigenetic) intervening factors can contribute toward the expression of PGK deficient clinical phenotypes.
format	article
author	Laurent R Chiarelli Simone M Morera Paola Bianchi Elisa Fermo Alberto Zanella Alessandro Galizzi Giovanna Valentini
author_facet	Laurent R Chiarelli Simone M Morera Paola Bianchi Elisa Fermo Alberto Zanella Alessandro Galizzi Giovanna Valentini
author_sort	Laurent R Chiarelli
title	Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
title_short	Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
title_full	Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
title_fullStr	Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
title_full_unstemmed	Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
title_sort	molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/d93d0e0dc7be47b7a472f97bea7ebc60
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Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.

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