Mutations in GMPPA Cause a Glycosylation Disorder Characterized by Intellectual Disability and Autonomic Dysfunction
| Autor: | J. Christopher Hennings, Yoshinao Wada, Christian A. Hübner, Ingo Kurth, Thorsten Marquardt, Christine Coubes, Dieter Vanderschaeghe, Kwame Anyane-Yeboa, Dusica Babovic-Vuksanovic, Emile Van Schaftingen, Reinhard Mühlenberg, Pierre Sarda, Christian Beetz, Antje K. Huebner, Alma Sikiric, Janine Altmüller, Rizwan Mumtaz, Jürgen Brämswig, Avraham Zeharia, Ammi Grahn, Peter Nürnberg, Arsalan Ahmad, Meera Malik, Guntram Borck, Saqib Mahmood, Katrin Koehler, Holger Thiele, Sebastian Gießelmann, Gudrun Nürnberg, Angela Huebner, Janine Reunert, Lina Basel-Vanagaite |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Adult
Guanosine Diphosphate Mannose medicine.medical_specialty Glycosylation Adolescent Nonsense mutation Genes Recessive Consanguinity Triple-A syndrome Biology Alacrima Young Adult chemistry.chemical_compound Report Intellectual Disability Internal medicine Intellectual disability Genetics medicine Adrenal insufficiency Humans Genetics(clinical) Child Genetics (clinical) Lacrimal Apparatus Diseases Homozygote Eye Diseases Hereditary medicine.disease Nucleotidyltransferases Pedigree Esophageal Achalasia Endocrinology chemistry Codon Nonsense Nervous System Diseases Guanosine diphosphate mannose Adrenal Insufficiency |
| Zdroj: | The American Journal of Human Genetics. 93:727-734 |
| ISSN: | 0002-9297 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|