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POMT2
protein O-mannosyltransferase 2
POMT2 is located on the long (q) arm of chromosome 14, at band 14q24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
POMT2 is located on chromosome 14 and encodes protein O-mannosyltransferase 2, a 750-amino-acid enzyme subunit that works together with POMT1 to form a functional enzyme complex. This complex is particularly abundant in skeletal muscle, developing brain tissue, and testes, where it performs a specialised form of protein modification called O-mannosylation. The enzyme adds mannose sugar molecules to the protein alpha-dystroglycan, a modification essential for connecting the interior scaffolding of cells to the surrounding extracellular matrix. When POMT2 function is disrupted, this critical link is weakened, leading to muscle deterioration and brain malformations that characterise congenital muscular dystrophies.
What the gene does
The POMT2 protein functions as one half of the protein O-mannosyltransferase enzyme complex, partnering with the POMT1 subunit to catalyse the transfer of mannose from dolichyl-phosphate-mannose onto hydroxyl groups of serine and threonine residues in target proteins. The primary substrate for this complex is alpha-dystroglycan, a protein that serves as a linchpin connecting the internal cytoskeleton of muscle and nerve cells to the extracellular matrix surrounding them. Without proper glycosylation by the POMT complex, alpha-dystroglycan cannot bind effectively to extracellular proteins such as laminin, compromising the structural integrity of tissues that experience mechanical stress. In skeletal muscle fibres, this glycosylation helps stabilise and protect cells during contraction cycles. In the developing brain, properly modified alpha-dystroglycan guides the migration of neurons to their correct positions, a process crucial for establishing normal brain architecture. The POMT complex belongs to a larger pathway of protein glycosylation that includes multiple enzymes, each adding or modifying sugar residues in a stepwise manner to create the functional glycan structures required for alpha-dystroglycan activity.
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Chromosome location
POMT2 is located at chromosomal position 14q24.3 on the long arm of chromosome 14. This region has been mapped through linkage studies in families affected by congenital muscular dystrophies, helping to localise the gene before its molecular identification. The gene spans multiple exons encoding the 750-amino-acid protein, with regulatory elements that control expression patterns across different tissue types during development and in adult life.
Protein structure
The POMT2 protein comprises 750 amino acids and contains several functional regions that contribute to its enzymatic activity. The N-terminal region includes a disordered segment spanning amino acids 1-23, which may facilitate protein-protein interactions or regulatory modifications. Three mannosyltransferase imperfect repeats (MIR domains) form the catalytic core of the enzyme: MIR 1 extends from amino acids 334-390, MIR 2 from amino acids 403-459, and MIR 3 from amino acids 464-521. These MIR domains are characteristic of the glycosyltransferase family and coordinate the binding of the sugar donor molecule and the target protein substrate, enabling the transfer of mannose onto alpha-dystroglycan. The precise arrangement of these domains determines substrate specificity and catalytic efficiency of the POMT complex.
Key variants
Pathogenic variants in POMT2 follow an autosomal recessive inheritance pattern, meaning that two altered copies of the gene are required to cause disease manifestations. The severity of the resulting condition correlates broadly with the degree of residual enzyme activity, with complete loss-of-function variants typically causing the most severe phenotypes such as Walker-Warburg syndrome, whilst variants that partially preserve enzyme function may lead to milder muscular dystrophy presentations.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
POMT2-related disorders encompass a spectrum of congenital muscular dystrophies characterised by muscle weakness, structural brain abnormalities, and often eye malformations. Walker-Warburg syndrome represents the most severe manifestation, presenting with profound muscle weakness, cobblestone lissencephaly (a malformation where neurons fail to migrate properly), and eye defects including retinal dysplasia and cataracts. Affected individuals typically experience life-limiting complications in infancy or early childhood. Milder variants in POMT2 can cause muscle-eye-brain disease, where affected children may survive into adolescence or early adulthood, or limb-girdle muscular dystrophy with predominantly muscle involvement and less severe brain findings. All these conditions result from insufficient glycosylation of alpha-dystroglycan due to reduced POMT complex activity.
- Walker-Warburg syndrome Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic POMT2 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
POMT2 appears on multiple NHS Genomic Medicine Service gene panels as a green-rated gene, reflecting strong evidence for its clinical validity in relevant disorders. It is included on panels for congenital muscular dystrophy (R79), intellectual disability (R29), cerebellar hypoplasia, malformations of cortical development, and structural eye disease (R36), amongst others. This broad panel membership reflects the multi-system nature of POMT2-related conditions, which can present through neuromuscular, neurological, ophthalmological, or metabolic pathways. The gene is also listed on the congenital disorders of glycosylation panel and the likely inborn error of metabolism panel (R98), recognising the underlying biochemical defect in glycosylation that drives disease pathology.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between POMT1 and POMT2?
POMT1 and POMT2 encode the two subunits that together form the functional protein O-mannosyltransferase enzyme complex. Both subunits are required for enzyme activity, and pathogenic variants in either gene can cause similar congenital muscular dystrophy phenotypes. They are separate genes located on different chromosomes but work as obligate partners in the same biochemical reaction.
Can POMT2 carriers have symptoms?
Carriers of a single pathogenic POMT2 variant typically do not show symptoms of muscular dystrophy because one functional copy of the gene provides sufficient enzyme activity for normal development. However, if two carriers have children together, each pregnancy has a 25% chance of inheriting both altered copies and developing a POMT2-related condition.
Are there treatments for POMT2-related muscular dystrophies?
Current management focuses on supportive care, including physiotherapy to maintain mobility, respiratory support when breathing muscles are affected, and monitoring for complications such as seizures or heart problems. Research into gene therapy and glycosylation-enhancing treatments is ongoing, but no curative therapies are currently available. Affected individuals benefit from coordinated care by specialists in neuromuscular disorders, neurology, and ophthalmology.