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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)727-734
Number of pages8
JournalAmerican Journal of Human Genetics
Volume93
Issue number4
DOIs
StatePublished - Oct 3 2013

Fingerprint

Guanosine Diphosphate Mannose
Glycosylation
Intellectual Disability
Esophageal Achalasia
Mutation
Congenital Disorders of Glycosylation
Dystroglycans
Limb-Girdle Muscular Dystrophies
Adrenal Insufficiency
Nonsense Codon
Glycolipids
Enzymes
Pedigree
Gait
Polysaccharides
Glycoproteins
mannose 1-phosphate guanylyltransferase
Alacrima

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Koehler, K., Malik, M., Mahmood, S., Gießelmann, S., Beetz, C., Hennings, J. C., ... Hübner, C. A. (2013). Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction. American Journal of Human Genetics, 93(4), 727-734. https://doi.org/10.1016/j.ajhg.2013.08.002

Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction. / Koehler, Katrin; Malik, Meera; Mahmood, Saqib; Gießelmann, Sebastian; Beetz, Christian; Hennings, J. Christopher; Huebner, Antje K.; Grahn, Ammi; Reunert, Janine; Nürnberg, Gudrun; Thiele, Holger; Altmüller, Janine; Nürnberg, Peter; Mumtaz, Rizwan; Babovic-Vuksanovic, Dusica; Basel-Vanagaite, Lina; Borck, Guntram; Brämswig, Jürgen; Mühlenberg, Reinhard; Sarda, Pierre; Sikiric, Alma; Anyane-Yeboa, Kwame; Zeharia, Avraham; Ahmad, Arsalan; Coubes, Christine; Wada, Yoshinao; Marquardt, Thorsten; Vanderschaeghe, Dieter; Van Schaftingen, Emile; Kurth, Ingo; Huebner, Angela; Hübner, Christian A.

In: American Journal of Human Genetics, Vol. 93, No. 4, 03.10.2013, p. 727-734.

Research output: Contribution to journalArticle

Koehler, K, Malik, M, Mahmood, S, Gießelmann, S, Beetz, C, Hennings, JC, Huebner, AK, 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 & Hübner, CA 2013, 'Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction', American Journal of Human Genetics, vol. 93, no. 4, pp. 727-734. https://doi.org/10.1016/j.ajhg.2013.08.002
Koehler, Katrin ; Malik, Meera ; Mahmood, Saqib ; Gießelmann, Sebastian ; Beetz, Christian ; Hennings, J. Christopher ; Huebner, Antje K. ; Grahn, Ammi ; Reunert, Janine ; Nürnberg, Gudrun ; Thiele, Holger ; Altmüller, Janine ; Nürnberg, Peter ; Mumtaz, Rizwan ; Babovic-Vuksanovic, Dusica ; Basel-Vanagaite, Lina ; Borck, Guntram ; Brämswig, Jürgen ; Mühlenberg, Reinhard ; Sarda, Pierre ; Sikiric, Alma ; Anyane-Yeboa, Kwame ; Zeharia, Avraham ; Ahmad, Arsalan ; Coubes, Christine ; Wada, Yoshinao ; Marquardt, Thorsten ; Vanderschaeghe, Dieter ; Van Schaftingen, Emile ; Kurth, Ingo ; Huebner, Angela ; Hübner, Christian A. / Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction. In: American Journal of Human Genetics. 2013 ; Vol. 93, No. 4. pp. 727-734.
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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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AU - Malik, Meera

AU - Mahmood, Saqib

AU - Gießelmann, Sebastian

AU - Beetz, Christian

AU - Hennings, J. Christopher

AU - Huebner, Antje K.

AU - Grahn, Ammi

AU - Reunert, Janine

AU - Nürnberg, Gudrun

AU - Thiele, Holger

AU - Altmüller, Janine

AU - Nürnberg, Peter

AU - Mumtaz, Rizwan

AU - Babovic-Vuksanovic, Dusica

AU - Basel-Vanagaite, Lina

AU - Borck, Guntram

AU - Brämswig, Jürgen

AU - Mühlenberg, Reinhard

AU - Sarda, Pierre

AU - Sikiric, Alma

AU - Anyane-Yeboa, Kwame

AU - Zeharia, Avraham

AU - Ahmad, Arsalan

AU - Coubes, Christine

AU - Wada, Yoshinao

AU - Marquardt, Thorsten

AU - Vanderschaeghe, Dieter

AU - Van Schaftingen, Emile

AU - Kurth, Ingo

AU - Huebner, Angela

AU - Hübner, Christian A.

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