Mannose-1-phosphate guanylyltransferase regulatory subunit alpha

GMPPA (mannose-1-phosphate guanylyltransferase regulatory subunit alpha) is a regulatory protein that forms a complex with GMPPB to modulate the catalytic activity of guanylyltransferase. The protein functions as an allosteric inhibitor, mediating feedback suppression of GMPPB activity through binding of GDP-alpha-D-mannose, thereby regulating cellular GDP-alpha-D-mannose levels (UniProt: Q96IJ6).

In humans, GMPPA is primarily associated with alacrima, achalasia, and intellectual disability (AAMR), an autosomal recessive neurodevelopmental disorder (UniProt: Q96IJ6). The condition presents with congenital alacrima and achalasia alongside intellectual impairment, with variable additional features including hypotonia and sensory deficits, distinguishing it from triple A syndrome by the absence of adrenal involvement.

In Alzheimer's disease, GMPPA shows upregulation in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of 0.60 across subcellular fractions analyzed by quantitative proteomics (Chaparral AD proteomics). This elevation suggests potential involvement in AD-associated pathophysiology, though the functional significance of increased GMPPA in disease remains to be elucidated.