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MTMR2
myotubularin related protein 2
MTMR2 is located on the long (q) arm of chromosome 11, at band 11q21. Arm ratio per GRCh38 - banding schematic.
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Overview
MTMR2 is located on chromosome 11 and encodes a member of the myotubularin phosphatase family. The protein it produces plays a vital role in regulating phosphoinositide metabolism within cells, particularly affecting membrane trafficking and cellular signalling pathways. Dysfunction of MTMR2 disrupts normal nerve cell biology, leading to progressive peripheral neuropathy.
Pathogenic variants in MTMR2 are associated with hereditary motor and sensory neuropathy, a group of inherited conditions affecting the peripheral nervous system. The gene is recognised in UK clinical genetics pathways for hereditary neuropathy assessment, reflecting its established role in nerve health and disease.
What the gene does
The MTMR2 protein functions as a lipid phosphatase, specifically targeting phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. By dephosphorylating these phosphoinositide molecules, MTMR2 helps control the balance of lipid signals that govern membrane identity, vesicle trafficking, and autophagy within cells.
This enzymatic activity is especially critical in Schwann cells of the peripheral nervous system. Schwann cells wrap around nerve axons to form myelin, a fatty insulating layer that allows electrical impulses to travel efficiently along nerves. MTMR2 contributes to maintaining the structural integrity of myelin and supporting the metabolic demands of these specialised glial cells. When MTMR2 function is compromised, Schwann cells cannot properly maintain myelin, resulting in demyelination and progressive nerve damage that manifests as muscle weakness, sensory loss, and gait abnormalities.
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Chromosome location
MTMR2 is located on the long arm of chromosome 11 at position 11q21. This chromosomal region contains multiple genes involved in diverse biological processes. The precise genomic coordinates and exon-intron structure of MTMR2 have been mapped, enabling targeted sequencing approaches for diagnostic testing in individuals with suspected hereditary neuropathy.
Protein structure
The MTMR2 protein comprises 643 amino acids and contains several functionally distinct regions. The N-terminal portion includes a disordered region (amino acids 1-56) followed by a GRAM domain (amino acids 68-139), which may contribute to membrane binding. The central core of the protein houses the myotubularin phosphatase domain (amino acids 205-580), which catalyses the removal of phosphate groups from phosphoinositide substrates and represents the enzyme's active site. Towards the C-terminus, a coiled-coil region (amino acids 593-627) likely mediates protein-protein interactions, enabling MTMR2 to form complexes with other cellular partners. The protein concludes with another disordered region (amino acids 615-643). This domain architecture supports both the catalytic function and the regulatory interactions necessary for MTMR2 to operate within complex cellular signalling networks.
Key variants
Pathogenic variants in MTMR2 typically result in loss of phosphatase activity or destabilisation of the protein. Variants are distributed across the gene, with several affecting the myotubularin phosphatase domain and disrupting enzymatic function. Both missense variants that alter critical residues and truncating variants that produce shortened, non-functional proteins have been documented. The clinical impact of specific variants can vary, and detailed variant interpretation often requires assessment of familial segregation and functional studies.
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.1090C>T | p.Arg364Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4 |
c.1318C>T | p.Arg440Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4B1 |
c.1362_1363del | p.Ser455fs | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4 |
c.1537_1538dup | p.Ser514fs | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4B1 |
c.1591G>T | p.Glu531Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1720G>T | p.Glu574Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4 |
c.1768C>T | p.Gln590Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4B1 |
c.304C>T | p.Arg102Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4B1 |
c.464_465del | p.Val154_Cys155insTer | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4 |
c.484C>T | p.Arg162Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4B1 |
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
Variants in MTMR2 cause autosomal recessive forms of Charcot-Marie-Tooth disease, specifically type 4B1. This hereditary neuropathy typically presents in childhood or adolescence with progressive weakness and wasting of muscles in the lower legs, followed by similar changes in the hands and forearms. Affected individuals may develop foot deformities, loss of sensation in the extremities, and difficulty walking. The condition results from demyelination of peripheral nerves, which impairs the transmission of electrical signals between the brain and muscles. Severity and progression can differ among individuals, even within the same family.
No disease links recorded for this gene in our reference set.
UK clinical status
MTMR2 is included as a green-rated gene on the NHS Genomic Medicine Service's Hereditary Neuropathy panel and the Hereditary Neuropathy or Pain Disorder panel (version R78). Green classification indicates robust evidence supporting the gene-disease association and its suitability for diagnostic use. Clinicians in the UK may request genomic testing for MTMR2 as part of evaluating patients with unexplained peripheral neuropathy or a family history suggestive of inherited nerve disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the MTMR2 gene do?
MTMR2 encodes a phosphatase enzyme that regulates lipid molecules in cell membranes, particularly in the Schwann cells that form myelin around peripheral nerves. This activity is essential for maintaining healthy nerve signal transmission.
How are MTMR2 variants inherited?
Pathogenic variants in MTMR2 are inherited in an autosomal recessive pattern, meaning an individual must inherit two altered copies (one from each parent) to develop symptoms. Carriers with one variant copy typically do not show signs of neuropathy.
Is testing for MTMR2 available on the NHS?
Yes, MTMR2 is included on NHS hereditary neuropathy testing panels for individuals meeting clinical criteria. A genetics specialist or neurologist can determine eligibility and arrange appropriate genomic testing through the NHS Genomic Medicine Service.