Koehler, Katrin ORCID: 0000-0002-9407-1410, Malik, Meera, Mahmood, Saqib, Giesselmann, Sebastian, Beetz, Christian ORCID: 0000-0001-7061-2895, Hennings, J. Christopher, Huebner, Antje K., Grahn, Ammi, Reunert, Janine, Nuernberg, Gudrun, Thiele, Holger, Altmueller, Janine, Nuernberg, Peter, Mumtaz, Rizwan, Babovic-Vuksanovic, Dusica, Basel-Vanagaite, Lina, Borck, Guntram, Braemswig, Jurgen, Muehlenberg, Reinhard, Sarda, Pierre, Sikiric, Alma, Anyane-Yeboa, Kwame ORCID: 0000-0002-4977-9719, Zeharia, Avraham, Ahmad, Arsalan, Coubes, Christine, Wada, Yoshinao, Marquardt, Thorsten, Vanderschaeghe, Dieter, Van Schaftingen, Emile ORCID: 0000-0002-6199-7647, Kurth, Ingo ORCID: 0000-0002-5642-8378, Huebner, Angela and Huebner, Christian A. (2013). Mutations in GMPPA Cause a Glycosylation Disorder Characterized by Intellectual Disability and Autonomic Dysfunction. Am. J. Hum. Genet., 93 (4). S. 727 - 735. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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 a-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Koehler, KatrinUNSPECIFIEDorcid.org/0000-0002-9407-1410UNSPECIFIED
Malik, MeeraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahmood, SaqibUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giesselmann, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beetz, ChristianUNSPECIFIEDorcid.org/0000-0001-7061-2895UNSPECIFIED
Hennings, J. ChristopherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huebner, Antje K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grahn, AmmiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reunert, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mumtaz, RizwanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Babovic-Vuksanovic, DusicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Basel-Vanagaite, LinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borck, GuntramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braemswig, JurgenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muehlenberg, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarda, PierreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sikiric, AlmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anyane-Yeboa, KwameUNSPECIFIEDorcid.org/0000-0002-4977-9719UNSPECIFIED
Zeharia, AvrahamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahmad, ArsalanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coubes, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wada, YoshinaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marquardt, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vanderschaeghe, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Schaftingen, EmileUNSPECIFIEDorcid.org/0000-0002-6199-7647UNSPECIFIED
Kurth, IngoUNSPECIFIEDorcid.org/0000-0002-5642-8378UNSPECIFIED
Huebner, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huebner, Christian A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-474275
DOI: 10.1016/j.ajhg.2013.08.002
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 93
Number: 4
Page Range: S. 727 - 735
Date: 2013
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GDP-MANNOSE PYROPHOSPHORYLASE; WD-REPEAT PROTEIN; TRIPLE-A SYNDROME; SACCHAROMYCES-CEREVISIAE; CONGENITAL DISORDERS; CRYSTAL-STRUCTURE; GENE; MECHANISMS; NEUROPATHY; MUTANTSMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47427

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