A mouse model for the human lysosomal disease aspartylglycosaminuria

Nature Medicine
V KaartinenJ Groffen

Abstract

Aspartylglycosaminuria (AGU), the most common disorder of glycoprotein degradation in humans, is caused by mutations in the gene encoding the lysosomal enzyme glycosylasparaginase (Aga). The resulting enzyme deficiency allows aspartylglucosamine (GlcNAc-Asn) and other glycoasparagines to accumulate in tissues and body fluids, from early fetal life onward. The clinical course is characterized by normal early development, slowly progressing to severe mental and motor retardation in early adulthood. The exact pathogenesis of AGU in humans is unknown and neither therapy nor an animal model for this debilitating and ultimately fatal disease exists. Through targeted disruption of the mouse Aga gene in embryonic stem cells, we generated mice that completely lack Aga activity. At the age of 5-10 months a massive accumulation of GlcNAc-Asn was detected along with lysosomal vacuolization, axonal swelling in the gracile nucleus and impaired neuromotor coordination. A significant number of older male mice had massively swollen bladders, which was not caused by obstruction, but most likely related to the impaired function of the nervous system. These findings are consistent with the pathogenesis of AGU and provide further data explaining th...Continue Reading

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Citations

Sep 22, 2001·Physiology & Behavior·A V AnagnostopoulosM T Davisson
Dec 3, 2016·Orphanet Journal of Rare Diseases·Maria Arvio, Ilkka Mononen
May 2, 2008·Journal of Neurosurgery·Paul A GardnerArlan H Mintz
Oct 3, 1998·The Journal of Biological Chemistry·T NoronkoskiI Mononen
Mar 9, 2020·Molecular Genetics and Genomics : MGG·Paul J DunnLyn R Griffiths
Mar 24, 2004·Journal of Neurosurgery·Giulio MairaAndrea Vignati
Mar 11, 2003·Human Genetics·Reijo Norio
Feb 5, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·U DunderI Mononen
Feb 11, 1998·Brain Pathology·K SuzukiK Suzuki
Nov 14, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Xin ChenSteven J Gray
May 16, 2017·Advanced Drug Delivery Reviews·Melani Solomon, Silvia Muro
Nov 26, 1999·Biochimica Et Biophysica Acta·N N Aronson

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