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MAN1B1
mannosidase alpha class 1B member 1
MAN1B1 is located on the long (q) arm of chromosome 9, at band 9q34.3. Arm ratio per GRCh38 - banding schematic.
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Overview
MAN1B1 encodes mannosidase alpha class 1B member 1, an enzyme that participates in the glycosylation pathway within cells. Glycosylation is the process by which sugar molecules are attached to proteins, influencing their stability, folding, and function. The MAN1B1 enzyme specifically removes mannose residues from glycoproteins during quality control in the endoplasmic reticulum, ensuring that only correctly folded proteins proceed through the secretory pathway. Variants in this gene can disrupt normal glycosylation, leading to a spectrum of metabolic and developmental conditions. MAN1B1-related disorders are inherited in an autosomal recessive manner, meaning two altered copies of the gene are required for clinical manifestations.
What the gene does
The MAN1B1 protein functions as an alpha-mannosidase, catalysing the removal of specific mannose sugar units from N-linked glycans attached to newly synthesised proteins in the endoplasmic reticulum. This enzymatic activity is essential for the endoplasmic reticulum-associated degradation pathway, a quality control system that identifies misfolded or improperly assembled proteins and targets them for destruction. By trimming mannose residues, MAN1B1 generates glycan structures that serve as recognition signals for cellular machinery responsible for protein degradation. Without functional MAN1B1 activity, aberrant glycoproteins may accumulate, leading to endoplasmic reticulum stress and impaired cellular function. The enzyme's role extends to maintaining cellular homeostasis and supporting normal development, particularly in tissues with high protein turnover or complex glycosylation requirements, such as the nervous system.
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Chromosome location
MAN1B1 is located on chromosome 9 at position 9q34.3, near the long arm terminus. This chromosomal region contains numerous genes involved in diverse cellular processes. The specific location on chromosome 9 places MAN1B1 within a gene-dense area, though the gene itself is relatively compact compared to some other members of the mannosidase family.
Protein structure
The MAN1B1 protein comprises 699 amino acids and contains a disordered region spanning amino acids 125 to 243. Disordered regions lack fixed three-dimensional structure and may facilitate protein-protein interactions or provide regulatory flexibility. The enzymatic active site responsible for mannose cleavage resides within structured portions of the protein, enabling precise substrate recognition and catalytic activity.
Key variants
Pathogenic variants in MAN1B1 typically result in reduced or absent enzyme activity, compromising the cell's ability to process glycoproteins correctly. Such variants may include missense changes that disrupt the active site, nonsense mutations leading to truncated protein, or splice-site alterations affecting messenger RNA processing. The severity of clinical features often correlates with residual enzyme function, though genotype-phenotype relationships remain an area of active investigation.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1000C>T | p.Arg334Cys | Pathogenic/Likely pathogenic | ★★☆☆ | MAN1B1-related disorder |
c.1075G>T | p.Gly359Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Rafiq syndrome |
c.1735dup | p.Gln579fs | Pathogenic/Likely pathogenic | ★★☆☆ | Rafiq syndrome |
c.1833_1834del | p.Asp613fs | Pathogenic/Likely pathogenic | ★★☆☆ | Rafiq syndrome |
c.484C>T | p.Gln162Ter | Pathogenic | ★★☆☆ | Rafiq syndrome |
c.1014dup | p.Leu339fs | Pathogenic | ★☆☆☆ | Rafiq syndrome |
c.1177_1178dup | p.Ser393fs | Pathogenic | ★☆☆☆ | Rafiq syndrome |
c.1216del | p.Arg406fs | Pathogenic | ★☆☆☆ | Rafiq syndrome |
c.1240dup | p.Asp414fs | Pathogenic | ★☆☆☆ | Rafiq syndrome |
c.297_301del | p.Phe100fs | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in MAN1B1 are linked to congenital disorders of glycosylation, a group of inherited metabolic conditions characterised by defective glycosylation of proteins and lipids. Affected individuals may present with intellectual disability, developmental delay, and metabolic disturbances. The spectrum of clinical severity varies, with some individuals experiencing profound developmental impairment while others exhibit milder features. These conditions reflect the critical importance of proper glycosylation for normal growth and neurological function.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MAN1B1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
MAN1B1 appears on multiple NHS Genomic Medicine Service gene panels with green (high-evidence) classification, including the Congenital Disorders of Glycosylation panel, the DDG2P developmental disorders panel, the Intellectual Disability panel, the Likely Inborn Error of Metabolism panel, and the Undiagnosed Metabolic Disorders panel. These designations indicate strong evidence supporting the gene's role in the respective clinical presentations and its inclusion in diagnostic testing pathways for individuals with compatible features.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does MAN1B1 do in the body?
MAN1B1 encodes an enzyme that removes mannose sugars from proteins during quality control in the endoplasmic reticulum. This trimming process helps cells identify and eliminate misfolded proteins, maintaining cellular health and proper protein function.
How are MAN1B1-related conditions inherited?
MAN1B1-related conditions follow an autosomal recessive inheritance pattern. An individual must inherit two altered copies of the gene, one from each parent, to develop the condition. Carriers with one altered copy typically show no symptoms.
Why is MAN1B1 included on NHS gene panels?
MAN1B1 appears on several NHS panels for congenital disorders of glycosylation, intellectual disability, and metabolic conditions because pathogenic variants in this gene are recognised causes of these clinical presentations. Panel inclusion supports diagnostic testing for affected individuals and families.