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

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 SardaAlma 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


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.

Original languageEnglish
Pages (from-to)727-734
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 3 Oct 2013


FundersFunder number
Israeli Ministry of Health Chief Scientist Foundation3-4963
Israeli Science Foundation558/09
Deutsche Forschungsgemeinschaft
Japan Society for the Promotion of Science23390081


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