title: 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.affiliation: Division of Endocrinology and Diabetes, Children's Hospital, Technical University Dresden, Dresden 01307, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Koehler
authors.forename: Meera
authors.initials: M
authors.lastname: Malik
authors.forename: Saqib
authors.initials: S
authors.lastname: Mahmood
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gießelmann
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Hennings
authors.forename: Antje K
authors.initials: AK
authors.lastname: Huebner
authors.forename: Ammi
authors.initials: A
authors.lastname: Grahn
authors.forename: Janine
authors.initials: J
authors.lastname: Reunert
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Rizwan
authors.initials: R
authors.lastname: Mumtaz
authors.forename: Dusica
authors.initials: D
authors.lastname: Babovic-Vuksanovic
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brämswig
authors.forename: Reinhard
authors.initials: R
authors.lastname: Mühlenberg
authors.forename: Pierre
authors.initials: P
authors.lastname: Sarda
authors.forename: Alma
authors.initials: A
authors.lastname: Sikiric
authors.forename: Kwame
authors.initials: K
authors.lastname: Anyane-Yeboa
authors.forename: Avraham
authors.initials: A
authors.lastname: Zeharia
authors.forename: Arsalan
authors.initials: A
authors.lastname: Ahmad
authors.forename: Christine
authors.initials: C
authors.lastname: Coubes
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Wada
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.forename: Dieter
authors.initials: D
authors.lastname: Vanderschaeghe
authors.forename: Emile
authors.initials: E
authors.lastname: Van Schaftingen
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000235:genetics; D000328:Adult; D002648:Child; D018389:Codon, Nonsense; D003241:Consanguinity; D004931:Esophageal Achalasia / Q000235:genetics; D015785:Eye Diseases, Hereditary / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics*; D006031:Glycosylation; D006155:Guanosine Diphosphate Mannose / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics*; D007766:Lacrimal Apparatus Diseases / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics; D009713:Nucleotidyltransferases / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D006155:Guanosine Diphosphate Mannose; D009713:Nucleotidyltransferases; C026917:mannose 1-phosphate guanylyltransferase
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