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GMPPA
GDP-mannose pyrophosphorylase A
GMPPA is located on the long (q) arm of chromosome 2, at band 2q35. Arm ratio per GRCh38 - banding schematic.
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Overview
GMPPA encodes GDP-mannose pyrophosphorylase A, an enzyme that participates in the biosynthesis of GDP-mannose, a nucleotide sugar crucial for protein glycosylation. Glycosylation is the process by which sugar molecules are attached to proteins, affecting their stability, function, and cellular localisation. The GMPPA protein works alongside other enzymes to ensure adequate GDP-mannose supply for various glycosylation pathways. Disruption of GMPPA function can impair the proper modification of numerous proteins throughout the body, contributing to developmental and metabolic abnormalities. Pathogenic variants in this gene are associated with congenital disorders of glycosylation, a group of inherited conditions characterised by defective protein and lipid glycosylation.
What the gene does
The GMPPA protein catalyses the conversion of mannose-1-phosphate and GTP into GDP-mannose and pyrophosphate, a reaction central to cellular carbohydrate metabolism. GDP-mannose serves as a mannose donor in the endoplasmic reticulum and Golgi apparatus, where it is used to build oligosaccharide chains attached to newly synthesised proteins. This enzyme functions as part of a metabolic pathway that supports both N-linked and O-linked glycosylation, processes essential for protein folding, quality control, and transport. The substrate-binding domain enables the enzyme to recognise and bind mannose-1-phosphate and GTP, positioning these molecules for catalysis. The hexapeptide repeat domain contributes to the overall structural stability of the protein and may influence substrate access or product release. Adequate GMPPA activity ensures that cells maintain sufficient GDP-mannose levels to meet the demands of ongoing protein synthesis and modification.
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Chromosome location
GMPPA is located on the long arm of chromosome 2 at position 2q35. This chromosomal region contains numerous genes, and its genomic organisation allows for coordinated regulation of GMPPA expression alongside neighbouring loci. The precise boundaries and exon structure of GMPPA contribute to the generation of messenger RNA transcripts that are translated into the functional enzyme.
Protein structure
The GMPPA protein is 420 amino acids in length and contains distinct structural regions that support its enzymatic function. The substrate-binding domain spans amino acids 2 to 251 and is responsible for recognising and binding the substrates mannose-1-phosphate and GTP during catalysis. The hexapeptide repeat domain extends from amino acids 273 to 420 and features repeated sequence motifs that provide structural stability and may modulate enzyme activity. Within the hexapeptide repeat domain, the C-loop region (amino acids 356 to 384) contributes to the three-dimensional architecture of the protein. These domains work together to enable efficient conversion of substrates into GDP-mannose, maintaining cellular glycosylation capacity.
Key variants
Pathogenic variants in GMPPA can reduce or eliminate the enzyme's ability to produce GDP-mannose, leading to insufficient availability of this critical sugar nucleotide. Such variants may include missense changes that alter amino acids essential for substrate binding or catalysis, as well as nonsense or frameshift variants that truncate the protein. The resulting deficiency in GDP-mannose disrupts normal protein glycosylation, affecting multiple cellular processes and organ systems.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Variants in GMPPA are recognised as a cause of congenital disorders of glycosylation, a heterogeneous group of inherited metabolic conditions. Individuals with GMPPA-related glycosylation disorders may present with intellectual disability, developmental delay, and features affecting the nervous system and other organs. The severity and specific clinical features can vary depending on the nature of the genetic variant and the degree of residual enzyme activity. These conditions are typically inherited in an autosomal recessive manner, meaning that affected individuals carry pathogenic variants on both copies of the gene.
No disease links recorded for this gene in our reference set.
UK clinical status
GMPPA is included on several NHS clinical panels used in the UK for genetic testing. The gene appears on the Congenital disorders of glycosylation panel, reflecting its established role in these conditions. It is also listed on the DDG2P (Developmental Disorders Genotype-to-Phenotype) panel, the Intellectual disability panel (R29), and the Likely inborn error of metabolism panel (R98). Additionally, GMPPA features on the Familial dysautonomia panel. These panel memberships indicate that pathogenic variants in GMPPA are clinically actionable within the NHS Genomic Medicine Service, guiding testing strategies for individuals with relevant clinical presentations.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the GMPPA gene do?
GMPPA encodes an enzyme that produces GDP-mannose, a sugar molecule used to attach carbohydrate chains to proteins during glycosylation. This process is essential for proper protein function throughout the body.
How are GMPPA-related conditions inherited?
GMPPA-related congenital disorders of glycosylation are typically inherited in an autosomal recessive pattern, meaning an affected individual has pathogenic variants on both copies of the gene, one inherited from each parent.
Is genetic testing for GMPPA available on the NHS?
Yes, GMPPA is included on multiple NHS clinical panels, including those for congenital disorders of glycosylation, intellectual disability, and inborn errors of metabolism, making testing available for individuals meeting appropriate clinical criteria.