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

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.

• Authors: Katrin Koehler, Meera Malik, Saqib Mahmood, Sebastian Gießelmann, Christian Beetz, J Christopher Hennings, Antje K Huebner, Ammi Grahn, Janine Reunert, Gudrun Nürnberg, Holger Thiele, Janine Altmüller, Peter Nürnberg, Rizwan Mumtaz, Dusica Babovic-Vuksanovic, Lina Basel-Vanagaite, Guntram Borck, Jürgen Brämswig, Reinhard Mühlenberg, Pierre Sarda, Alma Sikiric, Kwame Anyane-Yeboa, Avraham Zeharia, Arsalan Ahmad, Christine Coubes, Yoshinao Wada, Thorsten Marquardt, Dieter Vanderschaeghe, Emile Van Schaftingen, Ingo Kurth, Angela Huebner, Christian A Hübner
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 93 Issue 4 Pg. 727-34 (Oct 03 2013) ISSN: 1537-6605 [Electronic] United States
• PMID: 24035193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Codon, Nonsense
• Guanosine Diphosphate Mannose
• Nucleotidyltransferases
• mannose 1-phosphate guanylyltransferase

Topics

• Adolescent
• Adrenal Insufficiency (genetics)
• Adult
• Child
• Codon, Nonsense
• Consanguinity
• Esophageal Achalasia (genetics)
• Eye Diseases, Hereditary (genetics)
• Genes, Recessive (genetics)
• Glycosylation
• Guanosine Diphosphate Mannose (genetics, metabolism)
• Homozygote
• Humans
• Intellectual Disability (enzymology, genetics)
• Lacrimal Apparatus Diseases (genetics)
• Nervous System Diseases (genetics)
• Nucleotidyltransferases (genetics, metabolism)
• Pedigree
• Young Adult