Dominant inheritance of sialuria, an inborn error of feedback inhibition

American Journal of Human Genetics
Jules G LeroyW A Gahl

Abstract

"French type" sialuria, a presumably dominant disorder that, until now, had been documented in only five patients, manifests with mildly coarse facies, slight motor delay, and urinary excretion of large quantities (>1 g/d) of free N-acetylneuraminic acid (NeuAc). The basic defect consists of the very rare occurrence of failed feedback inhibition of a rate-limiting enzyme, in this case uridinediphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase, by a downstream product, in this case cytidine monophosphate (CMP)-NeuAc. We report a new patient with sialuria who has a heterozygous G-->A substitution in nucleotide 848 of the epimerase gene, which results in an R266Q change. The proband's other allele, as expected, had no mutation. However, the heterozygous R266Q mutation was detected in the patient's mother, who has similarly increased urinary levels of free NeuAc, thereby confirming, for the first time, the dominant mode of inheritance of this inborn error. The biochemical diagnosis of the proband was verified by the greatly increased level of free NeuAc in his cultured fibroblasts, the NeuAc distribution, mainly (59%) in the cytoplasm, and by the complete failure of 100 microM CMP-NeuAc to inhibit UDP-GlcNAc 2-epimerase activi...Continue Reading

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Citations

Jan 29, 2005·Current Neurology and Neuroscience Reports·Ikuya NonakaIchizo Nishino
Apr 1, 2008·Genetic Testing·Yadira Valles-AyoubDaniel Darvish
Feb 27, 2013·Genetic Testing and Molecular Biomarkers·Daniel NoDaniel Darvish
Jul 26, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Riko D KlootwijkMarjan Huizing
Jan 2, 2003·Genetics in Medicine : Official Journal of the American College of Medical Genetics·David A WengerShu-Ling Liu
Jun 15, 2011·Annual Review of Genomics and Human Genetics·Changsoo Kang, Dennis Drayna
Jan 6, 2016·American Journal of Medical Genetics. Part a·Megan Crone, Mary Ann Thomas
Jul 9, 2008·Trends in Molecular Medicine·Ajit Varki
May 7, 2014·Human Mutation·Frank V CelesteMarjan Huizing
May 5, 2016·Molecular Genetics and Metabolism·Neena L ChampaigneRoger E Stevenson
May 16, 2015·Molecular Neurobiology·Reema Singh, Ranjana Arya
Jun 14, 2006·Biochimica Et Biophysica Acta·Suzan WopereisRon A Wevers
Jul 15, 2009·Biochimica Et Biophysica Acta·Marjan Huizing, Donna M Krasnewich
Dec 15, 2016·Chembiochem : a European Journal of Chemical Biology·Denise KreuzmannKaya Bork
Jun 10, 2003·American Journal of Medical Genetics. Part a·Rick A MartinWilliam A Gahl
Jun 10, 2003·American Journal of Medical Genetics. Part a·Robert KletaWilliam A Gahl
Oct 20, 2018·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Nuria CarrilloMarjan Huizing
Apr 17, 2021·Neuroscience Letters·Marjan HuizingUNKNOWN FSASD Consortium

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