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POMT2
protein O-mannosyltransferase 2
The POMT2 gene provides instructions for a protein critical to the function of the protein O-mannosyltransferase (POMT) enzyme complex, which is essential for normal muscle and brain development. The POMT2 gene is integral to forming part of the POMT enzyme complex, which plays a key role in modifying alpha-dystroglycan through glycosylation.
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
The POMT2 gene, whose full name is protein O-mannosyltransferase 2, contains the genetic instructions for one component of the protein O-mannosyltransferase (POMT) enzyme complex. This enzyme complex is particularly abundant in specific tissues such as skeletal muscles, the foetal brain, and testes, underscoring its functional importance in these areas. The protein encoded by POMT2 works in conjunction with a protein derived from the POMT1 gene to form the complete enzyme complex.
What the gene does
The primary role of the POMT enzyme complex, which includes the protein produced by POMT2, is to attach a sugar molecule, mannose, to alpha-dystroglycan. This biochemical process, termed glycosylation, is essential for alpha-dystroglycan's proper activity. In muscle tissue, correctly glycosylated alpha-dystroglycan contributes to the stability and protection of muscle fibres by linking the internal cellular framework (cytoskeleton) to the external supporting structure (extracellular matrix). Within the brain, this protein guides the movement of nerve cells (neurons) during the initial stages of development. Impairments in this function can lead to various neurological and muscular conditions.
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Chromosome location
The POMT2 gene is situated on chromosome 14, specifically at band 14q24.3. This designation refers to its precise position on the long arm (q) of human chromosome 14.
Protein structure
The POMT2 protein comprises 750 amino acids. Structurally, it features a Disordered region located at amino acids 1-23. The protein also contains three distinct MIR (Mannosyltransferase, InterPro Domain) domains: MIR 1 spans amino acids 334-390, MIR 2 is found from amino acids 403-459, and MIR 3 covers amino acids 464-521. These domains are likely critical for the protein's enzymatic activity.
Key variants
Variants within the POMT2 gene can disrupt its ability to produce a functional protein, leading to impaired glycosylation of alpha-dystroglycan. Conditions associated with POMT2 are inherited in an autosomal recessive manner, meaning an individual typically needs to inherit two pathogenic variants, one from each parent, to develop a related condition. The range of clinical effects can vary depending on the specific variants involved.
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.1051del | p.Ala351fs | Pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 |
c.127A>T | p.Lys43Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 |
c.1786-2A>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 |
c.287A>G | p.Tyr96Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2 |
c.333+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2 |
c.333+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive limb-girdle muscular dystrophy type 2N |
c.435_438dup | p.Phe147fs | Pathogenic/Likely pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 |
c.786G>A | p.Trp262Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive limb-girdle muscular dystrophy |
c.816+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 |
c.824_825del | p.Val275fs | Pathogenic/Likely pathogenic | ★★☆☆ | POMT2-related disorder |
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 POMT2 gene are linked to a spectrum of inherited disorders, predominantly congenital muscular dystrophies. One of the most severe conditions associated with POMT2 variants is Walker-Warburg syndrome, which causes profound muscle weakness alongside abnormalities affecting the brain and eyes. Less severe forms of muscular dystrophy, such as muscle-eye-brain disease and POMT2-related congenital muscular dystrophy (also known as MDDGB2), are also connected to POMT2 variants, presenting with varying degrees of muscle and neurological involvement.
- 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
In the UK, the POMT2 gene is included in several NHS Genomic Medicine Service national test directory panels, indicating its clinical relevance for various conditions. It is listed as green for Arthrogryposis (R83), Ataxia and cerebellar anomalies - childhood onset, Cerebellar hypoplasia, Congenital disorders of glycosylation, Congenital muscular dystrophy (R79), DDG2P, Foetal anomalies (R21), Hydrocephalus (R86), Intellectual disability, Likely inborn error of metabolism (R98), Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies (R82), Malformations of cortical development, Structural eye disease (R36), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of the POMT2 gene?
The POMT2 gene provides instructions for a protein that is part of the POMT enzyme complex. This complex adds sugar molecules to alpha-dystroglycan, a protein essential for the stability of muscle fibres and the proper development of nerve cells in the brain.
What conditions are associated with POMT2 gene variants?
Variants in the POMT2 gene are associated with a spectrum of congenital muscular dystrophies, including severe conditions like Walker-Warburg syndrome, which affects muscles, brain, and eyes. Less severe forms, such as muscle-eye-brain disease and POMT2-related congenital muscular dystrophy, are also linked to this gene.
How are POMT2-related conditions inherited?
Conditions associated with the POMT2 gene are typically inherited in an autosomal recessive pattern. This means an individual usually needs to inherit two altered copies of the gene, one from each parent, to develop the condition.
References
- Saredi S, Gibertini S, Ardissone A. A fourth case of POMT2-related limb girdle muscle dystrophy with mild reduction of α-dystroglycan glycosylation. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2014. PMID: 24183756
- Yanagisawa A, Bouchet C, Quijano-Roy S. POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental retardation. European journal of medical genetics. 2009. PMID: 19138766
- 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
- van Reeuwijk J, Janssen M, van den Elzen C. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. Journal of medical genetics. 2005. PMID: 15894594
- 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