2. Academic Validation
  3. Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction

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

  • Am J Hum Genet. 2013 Oct 3;93(4):727-34. doi: 10.1016/j.ajhg.2013.08.002.
Katrin Koehler 1,  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
Affiliations

Affiliation

  • 1 Division of Endocrinology and Diabetes, Children's Hospital, Technical University Dresden, Dresden 01307, Germany.
PMID: 24035193 DOI: 10.1016/j.ajhg.2013.08.002
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.

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