GMPPB
GDP-Mannose Pyrophosphorylase B
Gene Information Card
| Symbol | GMPPB |
|---|---|
| Full Name | GDP-mannose pyrophosphorylase B |
| Gene Type | Protein coding |
| Chromosomal Location | 3p21.31 |
| NCBI Gene ID | 29925 ncbi.nlm.nih.gov/gene/29925 |
| Ensembl ID | ENSG00000173540 |
| UniProt ID | Q9Y5P6 |
| OMIM ID | 615320 |
| HGNC ID | 22932 |
| Aliases | MDDGA14, MDDGB14, MDDGC14 |
Description
The GMPPB gene encodes the beta subunit of GDP-mannose pyrophosphorylase, an enzyme that catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose. GDP-mannose is a key sugar donor for the glycosylation of proteins, including alpha-dystroglycan. Mutations in GMPPB impair protein O-mannosylation, leading to a spectrum of congenital muscular dystrophies and limb-girdle muscular dystrophies collectively known as dystroglycanopathies.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A14 (MDDGA14) | Loss-of-function mutations reduce GDP-mannose production, disrupting alpha-dystroglycan glycosylation and causing severe neurodevelopmental defects. | OMIM #615350 |
| Muscular dystrophy-dystroglycanopathy (congenital without mental retardation) type B14 (MDDGB14) | Hypomorphic GMPPB variants lead to partial glycosylation defects, resulting in milder congenital muscular dystrophy without significant brain involvement. | OMIM #615351 |
| Muscular dystrophy-dystroglycanopathy (limb-girdle) type C14 (MDDGC14) | Mild missense mutations cause late-onset limb-girdle muscular dystrophy with elevated creatine kinase and reduced alpha-dystroglycan glycosylation. | OMIM #615352 |
| Walker-Warburg syndrome | Severe biallelic GMPPB mutations can present with cobblestone lissencephaly, hydrocephalus, and eye anomalies. | ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skeletal muscle | 12.5 | Medium |
| Heart | 10.8 | Medium |
| Brain | 8.2 | Medium |
| Liver | 6.1 | Low |
| Kidney | 7.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Skeletal muscle myoblasts | 14.3 | High expression |
| Cardiomyocytes | 11.2 | Medium expression |
| Astrocytes | 9.5 | Medium expression |
| HepG2 | 5.8 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.79G>C (p.Asp27His) | Missense | Common in MDDGC14 | Reduces enzyme activity; impairs GDP-mannose synthesis |
| c.860G>A (p.Arg287Gln) | Missense | Recurrent in MDDGB14 | Partial loss of function; milder phenotype |
| c.1000G>A (p.Gly334Arg) | Missense | Rare | Severe reduction in GDP-mannose production; associated with MDDGA14 |
| c.1A>G (p.Met1Val) | Start loss | Rare | Complete loss of translation; severe congenital phenotype |
Mutation functional classification
Loss of Function (LOF)
Most GMPPB mutations are loss-of-function, reducing GDP-mannose pyrophosphorylase activity and impairing alpha-dystroglycan glycosylation.
Gain of Function (GOF)
No gain-of-function mutations reported.
Dominant Negative (DN)
No dominant-negative mutations reported; all pathogenic variants are recessive.
View complete mutation data：
Gene Ontology (GO)
| • GDP-mannose biosynthetic process (GO:0009298) | • GTP binding (GO:0005525) |
| • mannose-1-phosphate guanylyltransferase activity (GO:0004475) | • cytoplasm (GO:0005737) |
| • membrane (GO:0016020) |
Pathways
• GDP-mannose biosynthesis (Reactome: R-HSA-446219)
• O-linked glycosylation of alpha-dystroglycan (Reactome: R-HSA-5173105)
Protein Summary
GMPPB encodes the beta subunit of GDP-mannose pyrophosphorylase (GMPP), a heterodimeric enzyme that catalyzes the reversible conversion of mannose-1-phosphate and GTP to GDP-mannose and pyrophosphate. The beta subunit is essential for enzyme stability and activity. GDP-mannose is a critical substrate for the synthesis of dolichol-phosphate-mannose and for the O-mannosylation of alpha-dystroglycan, a key component of the dystrophin-glycoprotein complex. Defects in GMPPB lead to hypoglycosylation of alpha-dystroglycan, causing reduced binding to extracellular matrix ligands and resulting in muscular dystrophy with or without brain and eye involvement.
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