| Property | Value | [@guan2019] |----------|-------| [@hadjivassiliou2008] | Gene Symbol | TGM6 | [@gadoth2015] | Full Name | Transglutaminase 6 | [@inamdar2013] | Aliases | TG6, TGY | | Chromosomal Location | 20p13 | | NCBI Gene ID | [343641](https://www.ncbi.nlm.nih.gov/gene/343641) | | OMIM ID | [613900](https://omim.org/entry/613900) | | Ensembl ID | [ENSG00000166157](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000166157) | | UniProt ID | [O95932](https://www.uniprot.org/uniprot/O95932) | | Encoded Protein | [Transglutaminase 6 (TG6)](/proteins/tgm6-protein) | | Associated Diseases | [Spinocerebellar ataxia type 35 (SCA35)](/diseases/spinocerebellar-ataxia-type-35), gluten ataxia |
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Overview
TGM6 is a human gene whose product tGM6** encodes transglutaminase 6 (TG6), a member of the transglutaminase enzyme family. Transglutaminases are calcium-dependent enzymes that catalyze the formation of isopeptide bonds between glutamine and lysine residues in proteins, creating stable protein cross-links. TG6 is the most recently identified member of the transglutaminase family and is predominantly expressed in the central nervous system. Variants in TGM6 have been implicated in Spinocerebellar Ataxia Type 35 (SCA35), Gluten Ataxia, Relationship to Other Transglutaminase Diseases. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
Function
TGM6 encodes transglutaminase 6 (TG6), a member of the transglutaminase enzyme family. Transglutaminases are calcium-dependent enzymes that catalyze the formation of isopeptide bonds between glutamine and lysine residues in proteins, creating stable protein cross-links. TG6 is the most recently identified member of the transglutaminase family and is predominantly expressed in the central nervous system.
Key normal physiological functions include:
Protein cross-linking — Catalyzes calcium-dependent transamidation reactions, forming ε-(γ-glutamyl)lysine isopeptide bonds between substrate proteins in the CNS
Neuronal development — Involved in neuronal differentiation, neurite outgrowth, and cerebellar development, particularly during [Purkinje cell](/cell-types/purkinje-cells) maturation
Cytoskeletal organization — Cross-links cytoskeletal and structural proteins to maintain neuronal architecture and dendritic integrity
Protein homeostasis — Participates in post-translational modification of proteins that may regulate their stability and interactions
Cerebellar function — High expression in the cerebellum suggests a specific role in cerebellar circuitry and motor coordination
Disease Associations
Spinocerebellar Ataxia Type 35 (SCA35)
TGM6 mutations cause spinocerebellar ataxia type 35, an autosomal dominant progressive cerebellar ataxia:
First identified: Wang et al. (2010) mapped SCA35 to chromosome 20p13 in a Chinese family and identified TGM6 missense mutations
Mutations: Multiple missense mutations have been identified, including:
L517W — The first reported pathogenic mutation; disrupts catalytic core function
D327G — Disrupts calcium binding and enzyme activation
R111C — Affects the N-terminal β-sandwich domain
D598N — Alters the C-terminal β-barrel domains
Inheritance: Autosomal dominant
Age of onset: 40-60 years (mean ~50 years)
Prevalence: Rare; primarily reported in East Asian populations (Chinese, Japanese) but also in European families
Clinical features:
Progressive cerebellar [ataxia](/diseases/cerebellar-ataxia) affecting gait and limb coordination
Upper motor neuron signs (hyperreflexia, Babinski sign) in some patients
Tremor (postural and intention) in some families
Slow progression; patients often remain ambulatory for decades after onset
Neuropathology:
Cerebellar cortical atrophy, predominantly affecting the vermis
[Purkinje cell](/cell-types/purkinje-cells) loss with Bergmann gliosis
Mild neuronal loss in the dentate nucleus
No prominent extra-cerebellar pathology in most cases
Gluten Ataxia
TGM6 is a major autoantigen in gluten ataxia, a form of neurological gluten sensitivity:
Anti-TG6 antibodies — Patients with [celiac disease](/diseases/celiac-disease)-associated neurological manifestations develop IgA and IgG antibodies against TG6
Mechanism — Anti-TG6 antibodies cross the [blood-brain barrier](/entities/blood-brain-barrier), bind TG6 on cerebellar [neurons](/entities/neurons), and cause complement-dependent and antibody-dependent cytotoxicity
Prevalence — Anti-TG6 antibodies are found in ~70% of patients with gluten ataxia and ~30-40% of celiac disease patients with neurological symptoms
Treatment — Strict gluten-free diet reduces anti-TG6 antibody titers and can stabilize or improve ataxia symptoms
Differential diagnosis — Anti-TG6 serology helps distinguish gluten ataxia from other sporadic ataxias
Relationship to Other Transglutaminase Diseases
The transglutaminase family includes several disease-associated members:
Low/absent expression: Most peripheral tissues (distinguishing TG6 from the ubiquitous TG2)
Cellular expression: Predominantly [neurons](/cell-types/neurons); lower expression in [astrocytes](/cell-types/astrocytes) and [oligodendrocytes](/cell-types/oligodendrocytes)
Subcellular localization: Cytoplasmic, with membrane-associated pools; can be externalized to the cell surface
Developmental pattern: Expression increases during postnatal cerebellar development, peaking in the adult cerebellum
Gene Structure and Regulation
Gene size: ~37 kb spanning 13 exons
Transcript: ~3.0 kb mRNA encoding a 706-amino acid protein
Alternative splicing: Multiple transcript variants have been identified, with the full-length isoform being the dominant form in the brain
Promoter: Contains neuron-specific regulatory elements including NeuroD and NRSF/REST binding sites
Evolutionary conservation: TGM6 is well-conserved in mammals; orthologues are present in all vertebrates
Animal Models
Tgm6 knockout mice — Show progressive motor dysfunction, cerebellar atrophy, and Purkinje cell loss, recapitulating key features of SCA35
L517W knock-in mice — Develop age-dependent ataxia with perinuclear TG6 aggregates and endoplasmic reticulum stress in Purkinje cells
Drosophila models — Expression of mutant TG6 in fly neurons causes locomotor deficits and neurodegeneration
Zebrafish models — Morpholino knockdown of tgm6 results in abnormal cerebellar development and motor deficits
Pathogenic Mechanisms
SCA35-causing TGM6 mutations lead to neurodegeneration through several pathways:
Loss of enzymatic function — Missense mutations reduce transglutaminase activity, impairing neuronal protein cross-linking and cytoskeletal integrity
Protein misfolding and aggregation — Mutant TG6 forms perinuclear aggregates that trigger [endoplasmic reticulum stress](/mechanisms/endoplasmic-reticulum-stress) and the [unfolded protein response](/mechanisms/er-stress-unfolded-protein-response)
Impaired [autophagy](/entities/autophagy) — Mutant TG6 aggregates are cleared by [autophagy](/mechanisms/autophagy); chronic aggregate burden overwhelms autophagic capacity
Mitochondrial dysfunction — TG6 interacts with mitochondrial proteins; mutations disrupt mitochondrial membrane potential and increase oxidative stress
Calcium dysregulation — As a calcium-dependent enzyme, mutant TG6 with altered calcium sensitivity may disrupt calcium homeostasis in Purkinje cells
Therapeutic Implications
Enzyme replacement — Restoring TG6 catalytic activity could compensate for loss-of-function mutations
Protein homeostasis — Enhancing [autophagy](/mechanisms/autophagy) or chaperone function may promote clearance of mutant TG6 aggregates
Gluten-free diet — Effective for gluten ataxia (autoimmune TG6 targeting) but not for genetic SCA35
[Wang et al., TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing (2010) (2010)](https://doi.org/10.1093/brain/awq323)
[Hadjivassiliou et al., Transglutaminase 6 antibodies in the diagnosis of gluten ataxia (2013) (2013)](https://doi.org/10.1212/WNL.0b013e3182a1eae4)
[Li et al., TGM6 gene mutation in patients with spinocerebellar ataxia type 35 (2020) (2020)](https://doi.org/10.1016/j.parkreldis.2020.01.014)
[Tripathy et al., Mutations in TGM6 induce the unfolded protein response in SCA35 (2017) (2017)](https://doi.org/10.1093/hmg/ddx227)
[Guan et al., Spinocerebellar ataxia type 35 (SCA35): a review and call to action (2019) (2019)](https://doi.org/10.1002/mds.27833)
[Hadjivassiliou et al., Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase (2008) (2008)](https://doi.org/10.1002/ana.21450)
[Gadoth et al., Transglutaminase 6 antibodies in the diagnosis of gluten-related neurological dysfunction (2015) (2015)](https://doi.org/10.1111/ene.12647)
[Inamdar et al., Transglutaminase 6 expression in the central nervous system of mouse is developmentally regulated (2013) (2013)](https://doi.org/10.1016/j.neuint.2013.06.003)