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POMT1
protein O-mannosyltransferase 1
The POMT1 gene provides instructions for a component of the protein O-mannosyltransferase (POMT) enzyme complex, which is vital for proper muscle and brain development. The POMT1 gene is crucial for producing one part of the POMT enzyme complex.
POMT1 is located on the long (q) arm of chromosome 9, at band 9q34.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The POMT1 gene codes for protein O-mannosyltransferase 1, a key part of an enzyme complex known as protein O-mannosyltransferase (POMT). This enzyme complex is widely distributed throughout the body but is particularly abundant in skeletal muscles, the foetal brain, and the testes. The POMT complex plays a critical role in glycosylation, a process where sugar molecules are added to other proteins.
Specifically, the POMT complex adds a mannose sugar molecule to alpha-dystroglycan. This modification is fundamental for alpha-dystroglycan's proper function, impacting muscle stability and neurological development.
What the gene does
The protein encoded by the POMT1 gene forms one part of the essential protein O-mannosyltransferase (POMT) enzyme complex, with the other part being produced from the POMT2 gene. This complex is responsible for modifying alpha-dystroglycan, a protein that links the internal cellular structure to the extracellular matrix. The modification involves the addition of a mannose sugar molecule through a process known as glycosylation.
In skeletal muscles, correctly glycosylated alpha-dystroglycan is vital for stabilising and protecting muscle fibres. In the brain, this modified protein is involved in directing the migration of nerve cells during early developmental stages. Defects in this glycosylation process, often due to variants in POMT1, can lead to significant functional impairments in both muscle and brain tissues.
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Chromosome location
The POMT1 gene is located on chromosome 9. Its precise genomic address is 9q34.13, which refers to band 13 on the long (q) arm of chromosome 9. This specific location helps in mapping and understanding the genetic context of conditions associated with POMT1.
Protein structure
The POMT1 protein is composed of 747 amino acids. It features distinct protein domains that are important for its function. These include three MIR domains: MIR 1, located at amino acid positions 318-381; MIR 2, found between positions 392-449; and MIR 3, situated from amino acids 453-513. These domains are crucial for the protein's enzymatic activity and its interaction with other proteins.
Key variants
Variants within the POMT1 gene can alter the protein's structure and function, leading to impaired activity of the POMT enzyme complex. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions. Such alterations can disrupt the critical glycosylation process that POMT1 is involved in, thereby affecting proteins like alpha-dystroglycan.
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.Arg334Ter | Pathogenic/Likely pathogenic | ★★☆☆ | POMT1-related disorder |
c.1195dup | p.Leu399fs | Pathogenic/Likely pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
c.1284_1285del | p.Asn428fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive limb-girdle muscular dystrophy type 2K |
c.1524dup | p.Pro509fs | Pathogenic/Likely pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 |
c.162C>A | p.Tyr54Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
c.1724_1725del | p.Ile575fs | Pathogenic/Likely pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
c.1977del | p.Gln660fs | Pathogenic/Likely pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
c.2090_2093del | p.Leu697fs | Pathogenic/Likely pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
c.2142del | p.Arg713_Trp714insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 |
c.291del | p.Ser97fs | Pathogenic | ★★☆☆ | Walker-Warburg congenital muscular dystrophy |
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
Pathogenic variants in the POMT1 gene are primarily associated with a spectrum of congenital muscular dystrophies, with varying degrees of severity. The most severe condition linked to POMT1 variants is Walker-Warburg syndrome, characterised by significant muscle weakness and abnormalities affecting the brain and eyes. Other, less severe forms include muscle-eye-brain disease and POMT1-related congenital muscular dystrophy.
- Walker-Warburg syndrome Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic POMT1 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
The POMT1 gene is recognised within the NHS Genomic Medicine Service due to its association with several conditions. It is included on numerous PanelApp panels, indicating its clinical relevance for genetic testing in the UK. These panels cover a range of conditions including Arthrogryposis, Ataxia and cerebellar anomalies - childhood onset, Congenital disorders of glycosylation, Congenital muscular dystrophy, Foetal anomalies, Hydrocephalus, Intellectual disability, and Retinal disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the POMT1 gene?
The POMT1 gene provides instructions for a component of the protein O-mannosyltransferase (POMT) enzyme complex, which adds sugar molecules to alpha-dystroglycan, a protein essential for muscle stability and brain development.
What conditions are associated with variants in the POMT1 gene?
Variants in the POMT1 gene are linked to several forms of congenital muscular dystrophy, most notably Walker-Warburg syndrome, which causes severe muscle weakness and abnormalities in the brain and eyes.
How does POMT1 affect alpha-dystroglycan?
The POMT1 enzyme complex adds a mannose sugar molecule to alpha-dystroglycan. This glycosylation is crucial for alpha-dystroglycan's function in anchoring cellular structures and its role in nerve cell migration during development.
References
- Bello L, Melacini P, Pezzani R. Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy. European journal of human genetics : EJHG. 2012. PMID: 22549409
- Lommel M, Cirak S, Willer T. Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies. Neurology. 2010. PMID: 20065251
- Akasaka-Manya K, Manya H, Nakajima A. Physical and functional association of human protein O-mannosyltransferases 1 and 2. The Journal of biological chemistry. 2006. PMID: 16698797
- Balci B, Uyanik G, Dincer P. An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. Neuromuscular disorders : NMD. 2005. PMID: 15792865
- Manya H, Chiba A, Yoshida A. Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. Proceedings of the National Academy of Sciences of the United States of America. 2004. PMID: 14699049
- Kim DS, Hayashi YK, Matsumoto H. POMT1 mutation results in defective glycosylation and loss of laminin-binding activity in alpha-DG. Neurology. 2004. PMID: 15037715
- Akasaka-Manya K, Manya H, Endo T. Mutations of the POMT1 gene found in patients with Walker-Warburg syndrome lead to a defect of protein O-mannosylation. Biochemical and biophysical research communications. 2004. PMID: 15522202