Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction

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Item Type:	Article
Title:	Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction
Creators Name:	Koehler, K., Malik, M., Mahmood, S., Gießelmann, S., Beetz, C., Hennings, J.C., Huebner, A.K., Grahn, A., Reunert, J., Nürnberg, G., Thiele, H., Altmüller, J., Nürnberg, P., Mumtaz, R., Babovic-Vuksanovic, D., Basel-Vanagaite, L., Borck, G., Brämswig, J., Mühlenberg, R., Sarda, P., Sikiric, A., Anyane-Yeboa, K., Zeharia, A., Ahmad, A., Coubes, C., Wada, Y., Marquardt, T., Vanderschaeghe, D., Van Schaftingen, E., Kurth, I., Huebner, A. and Hübner, C.A.
Abstract:	In guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima, delayed developmental milestones, and gait abnormalities in a consanguineous Pakistani pedigree. Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia, alacrima, and neurological deficits. This autosomal-recessive disorder shows many similarities with triple A syndrome, which is characterized by achalasia, alacrima, and variable neurological deficits in combination with adrenal insufficiency. GMPPA is a largely uncharacterized homolog of GMPPB. GMPPB catalyzes the formation of GDP-mannose, which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-dystroglycan. Surprisingly, GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations. This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself. Thus, a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation, in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism.
Keywords:	Adrenal Insufficiency, Consanguinity, Esophageal Achalasia, Glycosylation, Guanosine Diphosphate Mannose, Hereditary Eye Diseases, Homozygote, Intellectual Disability, Lacrimal Apparatus Diseases, Nervous System Diseases, Nonsense Codon, Nucleotidyltransferases, Pedigree, Recessive Genes, Young Adult
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	93
Number:	4
Page Range:	727-734
Date:	3 October 2013
Official Publication:	https://doi.org/10.1016/j.ajhg.2013.08.002
PubMed:	View item in PubMed

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