Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction
Autor/innen
- K. Koehler
- M. Malik
- S. Mahmood
- S. Gießelmann
- C. Beetz
- J.C. Hennings
- A.K. Huebner
- A. Grahn
- J. Reunert
- G. Nürnberg
- H. Thiele
- J. Altmüller
- P. Nürnberg
- R. Mumtaz
- D. Babovic-Vuksanovic
- L. Basel-Vanagaite
- G. Borck
- J. Brämswig
- R. Mühlenberg
- P. Sarda
- A. Sikiric
- K. Anyane-Yeboa
- A. Zeharia
- A. Ahmad
- C. Coubes
- Y. Wada
- T. Marquardt
- D. Vanderschaeghe
- E. Van Schaftingen
- I. Kurth
- A. Huebner
- C.A. Hübner
Journal
- American Journal of Human Genetics
Quellenangabe
- Am J Hum Genet 93 (4): 727-734
Zusammenfassung
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.