TGM6 Gene

title: TGM6 Gene

TGM6 (Transglutaminase 6)

<div class="infobox infobox-gene"> [@tripathy2017]

| 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 |

</div>

Overview

title: TGM6 Gene

TGM6 (Transglutaminase 6)

<div class="infobox infobox-gene"> [@tripathy2017]

| 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 |

</div>

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

• Progressive cerebellar [ataxia](/diseases/cerebellar-ataxia) affecting gait and limb coordination
• Dysarthria and scanning speech
• Oculomotor abnormalities (saccadic pursuit, nystagmus)
• 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

• 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:

| Gene | Protein | Disease Association |
|------|---------|---------------------|
| TGM6 | TG6 | SCA35, gluten ataxia |
| TGM2 | [TG2](/proteins/tg2-protein) | Celiac disease (autoantigen), neurodegeneration |
| TGM1 | TG1 | Lamellar ichthyosis |
| TGM3 | TG3 | Dermatitis herpetiformis |
| TGM5 | TG5 | Acral peeling skin syndrome |
| F13A1 | Factor XIIIa | Bleeding disorder |

Expression

TGM6 expression is largely brain-specific:

• High expression: Cerebellum ([Purkinje cells](/cell-types/purkinje-cells), granule cell layer), cerebral [cortex](/brain-regions/cortex)
• Moderate expression: Brainstem, [hippocampus](/brain-regions/hippocampus), thalamus
• 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:

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
• Anti-TG6 antibody depletion — B-cell depleting therapies may benefit gluten ataxia patients
• Gene therapy — AAV-mediated delivery of wild-type TGM6 to the cerebellum is under early investigation

See Also

• [TGM6 Protein](/proteins/tgm6-protein)
• [Spinocerebellar ataxia type 35 (SCA35)](/diseases/spinocerebellar-ataxia-type-35)
• [ataxia](/diseases/cerebellar-ataxia)
• [celiac disease](/diseases/celiac-disease)
• [endoplasmic reticulum stress](/mechanisms/endoplasmic-reticulum-stress)
• [unfolded protein response](/mechanisms/er-stress-unfolded-protein-response)
• [autophagy](/mechanisms/autophagy)

External Links

• [NCBI Gene: TGM6](https://www.ncbi.nlm.nih.gov/gene/343641)
• [Ensembl: ENSG00000166157](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000166157)
• [UniProt: O95932](https://www.uniprot.org/uniprot/O95932)
• [GeneCards: TGM6](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TGM6)
• [OMIM: TGM6](https://omim.org/search?search=TGM6)
• [Allen Brain Atlas: TGM6](https://human.brain-map.org/microarray/search/show?search_term=TGM6)

References