Mutations in GMPPA Cause a Glycosylation Disorder Characterized by Intellectual Disability and Autonomic Dysfunction
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- 作者：Katrin Koehler ; Meera Malik ; Saqib Mahmood ; Sebastian Gie?elmann ; Christian Beetz ; J.?Christopher Hennings ; Antje?K. Huebner ; Ammi Grahn ; Janine Reunert ; Gudrun N¨¹rnberg ; Holger Thiele ; Janine Altm¨¹ller ; Peter N¨¹rnberg ; Rizwan Mumtaz ; Dusica Babovic-Vuksanovic ; Lina Basel-Vanagaite ; Guntram Borck ; J¨¹rgen Br?mswig ; Reinhard M¨¹hlenberg ; Pierre Sarda ; et al.
- 刊名：The American Journal of Human Genetics
- 出版年：2013
- 出版时间：3 October, 2013
- 年：2013
- 卷：93
- 期：4
- 页码：727-734
- 全文大小：642 K
文摘
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 ¦Á-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.