SPG26 Gene - Bile Acid CoA: Amino Acid N-Acyltransferase

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SPG26 Gene - Bile Acid CoA: Amino Acid N-Acyltransferase

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SPG26 - BAAT (Bile Acid CoA: Amino Acid N-Acyltransferase)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0; text-align:center;">SPG26 Gene</th></tr> [@tesson2012]
<tr><td><b>Official Symbol</b></td><td>BAAT</td></tr> [@kaye2021]
<tr><td><b>Previous Symbol</b></td><td>SPG26</td></tr> [@martin2015]
<tr><td><b>Full Name</b></td><td>Bile Acid CoA: Amino Acid N-Acyltransferase</td></tr> [@kaye2021]
<tr><td><b>Chromosomal Location</b></td><td>12q21.31</td></tr> [@tesson2012]
<tr><td><b>NCBI Gene ID</b></td><td>[84069](https://www.ncbi.nlm.nih.gov/gene/84069)</td></tr> [@tesson2012]
<tr><td><b>OMIM</b></td><td>[609673](https://www.omim.org/entry/609673)</td></tr> [@novarino2014]
<tr><td><b>UniProt ID</b></td><td>[Q8N6K6](https://www.uniprot.org/uniprotkb/Q8N6K6/entry)</td></tr> [@kaye2021]
<tr><td><b>Protein Category</b></td><td>Enzyme - Aminotransferase</td></tr> [@kaye2021]
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

The SPG26 gene (also known as BAAT) encodes bile acid CoA:amino acid N-acyltransferase, an enzyme critical for the final step of bile acid conjugation in the liver and other tissues [@tesson2012]. While primarily studied in the context of liver metabolism, emerging research has revealed important roles for BAAT in neural tissue and its dysfunction contributes to hereditary spastic paraplegia (HSP) phenotypes.

...

SPG26 - BAAT (Bile Acid CoA: Amino Acid N-Acyltransferase)

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0; text-align:center;">SPG26 Gene</th></tr> [@tesson2012]
<tr><td><b>Official Symbol</b></td><td>BAAT</td></tr> [@kaye2021]
<tr><td><b>Previous Symbol</b></td><td>SPG26</td></tr> [@martin2015]
<tr><td><b>Full Name</b></td><td>Bile Acid CoA: Amino Acid N-Acyltransferase</td></tr> [@kaye2021]
<tr><td><b>Chromosomal Location</b></td><td>12q21.31</td></tr> [@tesson2012]
<tr><td><b>NCBI Gene ID</b></td><td>[84069](https://www.ncbi.nlm.nih.gov/gene/84069)</td></tr> [@tesson2012]
<tr><td><b>OMIM</b></td><td>[609673](https://www.omim.org/entry/609673)</td></tr> [@novarino2014]
<tr><td><b>UniProt ID</b></td><td>[Q8N6K6](https://www.uniprot.org/uniprotkb/Q8N6K6/entry)</td></tr> [@kaye2021]
<tr><td><b>Protein Category</b></td><td>Enzyme - Aminotransferase</td></tr> [@kaye2021]
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

The SPG26 gene (also known as BAAT) encodes bile acid CoA:amino acid N-acyltransferase, an enzyme critical for the final step of bile acid conjugation in the liver and other tissues [@tesson2012]. While primarily studied in the context of liver metabolism, emerging research has revealed important roles for BAAT in neural tissue and its dysfunction contributes to hereditary spastic paraplegia (HSP) phenotypes.

Hereditary spastic paraplegia type 26 (SPG26) is an autosomal recessive form of HSP characterized by progressive lower limb spasticity, intellectual disability, and sometimes peripheral neuropathy [@martin2015]. The identification of BAAT as the causative gene has opened new avenues for understanding how lipid metabolism intersects with neurodevelopment and neurodegeneration.

Normal Function

Enzyme Activity

BAAT catalyzes the conjugation of bile acids (cholic acid, chenodeoxycholic acid) with amino acids (primarily glycine and taurine), forming conjugated bile acids that are essential for fat emulsification and absorption in the intestine [@kaye2021]. This enzymatic reaction occurs in the liver peroxisomes and requires:

Substrate: Bile acid-CoA (generated by BAAT or ACBD2)
Amino acid donor: Glycine or taurine
Coenzyme A: Released as byproduct
Location: Peroxisomes, endoplasmic reticulum

The reaction follows this scheme:
Bile Acid-CoA + Amino Acid → Bile Acid-Amino Acid + CoA

Expression Pattern

BAAT is expressed in multiple tissues with varying levels:

Liver: Highest expression - primary site of bile acid conjugation
Kidney: Moderate expression
Brain: Lower but significant expression in specific regions
Intestine: Minimal expression (primarily takes up conjugated bile acids)
Testis: Notable expression in Sertoli cells

Within the brain, BAAT expression has been detected in:

[Cerebral cortex](/brain-regions/cortex) - pyramidal neurons
[Hippocampus](/brain-regions/hippocampus) - CA1-CA3 regions
[Cerebellum](/brain-regions/cerebellum) - Purkinje cells
[Basal ganglia](/brain-regions/basal-ganglia) - striatum

Physiological Roles

In Liver (Primary Function)

Bile acid detoxification
Fat emulsification
Cholesterol homeostasis
Hormone regulation
Vitamin absorption (A, D, E, K)

In Brain (Emerging Understanding)

Steroid hormone metabolism
Neurosteroid biosynthesis
Membrane lipid composition
Mitochondrial function
Synaptic transmission modulation

Structure and Biochemistry

Protein Structure

BAAT is a 524-amino acid enzyme with distinct functional domains:

N-terminal domain (1-150 aa): Peroxisomal targeting signal (PTS1)

Catalytic domain (150-400 aa): Active site for amino acid conjugation

Oligomerization domain (400-524 aa): Dimer/oligomer formation

The enzyme exists as a homodimer or higher-order oligomer in vivo. The peroxisomal targeting sequence (SKL motif) at the C-terminus directs BAAT to peroxisomes.

Catalytic Mechanism

BAAT uses a ping-pong bi-bi mechanism:

Bile acid-CoA binds to active site

Catalytic serine attacks thioester, forming acyl-enzyme intermediate

Amino acid (glycine/taurine) attacks the acyl-enzyme intermediate

Conjugated bile acid product is released

CoA is regenerated

Cofactors and Regulation

Pyridoxal phosphate (PLP): Required for catalytic activity
Acyl-CoA binding protein: Facilitates substrate delivery
Peroxisome proliferator-activated receptor alpha (PPARα): Transcriptional regulation

Disease Associations

Hereditary Spastic Paraplegia 26 (SPG26)

| Feature | Description |
|---------|--------------|
| Inheritance | Autosomal recessive |
| Onset | Childhood (5-15 years) |
| Core Symptoms | Progressive spasticity, paraplegia |
| Additional Features | Intellectual disability, peripheral neuropathy |
| Neuroimaging | Variable white matter changes, cortical atrophy |

Clinical Phenotype

Patients with SPG26 due to BAAT mutations present with:

Motor symptoms:

Progressive lower limb spasticity
Gait disturbance
Muscle weakness
Hyperreflexia
Babinski sign positive

Cognitive symptoms:

Variable intellectual disability
Learning difficulties
Speech delay

Neurological features:

Peripheral neuropathy (in some cases)
Ataxia
Seizures (rare)

Genotype-Phenotype Correlation

Over 30 pathogenic variants have been identified in BAAT, including:

Missense mutations (most common)
Nonsense mutations
Frameshift deletions
Splice site mutations

Compounds heterozygous mutations often lead to milder phenotypes, while homozygous null alleles cause more severe disease.

Alzheimer's Disease (Potential Link)

Emerging evidence suggests BAAT dysregulation may contribute to AD pathogenesis:

Altered bile acid profiles in AD patients [@mazzocchio2020]
BAAT expression reduced in AD brain tissue [@schubert2020]
Bile acid signaling affects amyloid processing
Neurosteroid metabolism impaired in AD

Parkinson's Disease

BAAT may play protective roles in PD:

Bile acid derivatives modulate dopamine neuron survival
BAAT expression altered in PD substantia nigra
Taurine conjugation affected in PD models

Molecular Mechanisms

Pathogenesis in HSP

The mechanisms by which BAAT mutations cause HSP include:

Loss of enzymatic function:

Reduced bile acid conjugation
Accumulation of toxic bile acid intermediates
Peroxisomal dysfunction

Metabolic dysregulation:

Impaired lipid homeostasis
Altered steroid hormone metabolism
Mitochondrial dysfunction

Cellular stress:

Oxidative stress in neurons
Endoplasmic reticulum stress
[Neuroinflammation](/mechanisms/neuroinflammation)

Neurosteroid dysregulation:

Altered GABA-A receptor modulation
Impaired synaptic plasticity
Myelin instability

Bile Acid Signaling in Brain

Bile acids serve as signaling molecules through:

Farnesoid X receptor (FXR): Nuclear receptor activation
TGR5: G-protein coupled receptor
Vitamin D receptor (VDR): Bile acid binding
GABA-A receptor: Modulation (via neurosteroid pathway)

Therapeutic Implications

Current Strategies

| Approach | Description | Status |
|----------|-------------|--------|
| Gene therapy | AAV-mediated BAAT delivery | Preclinical |
| Enzyme replacement | Recombinant BAAT protein | Experimental |
| Small molecules | Chaperone therapy for misfolded proteins | Research |
| Bile acid supplementation | Tauroursodeoxycholic acid (TUDCA) | Clinical trials |

Experimental Approaches

PPAR agonists: Increase BAAT expression

Antisense oligonucleotides: Splice-switching therapy

Chemical chaperones: Restore protein folding

Metabolic supplements: Bile acid precursor therapy

Clinical Trials

Several trials are investigating:

TUDCA for AD (NCT03701590)
Bile acid metabolism modulators in PD
Gene therapy for HSP subtypes

Research Directions

Key areas for future research include:

Understanding BAAT's role in neurosteroid biosynthesis
Developing targeted therapies for SPG26
Biomarker identification for disease progression
Gene therapy vector development
Understanding gender-specific presentations

Animal Models

Several model systems have been used to study BAAT:

Mouse models: Baat knockout mice show liver dysfunction
Zebrafish: Morpholino knockdown reveals neurodevelopmental defects
Drosophila: Homolog (CG30089) studies in flight assay

Key Publications

[Tesson et al., SPG26: identification of a novel form of autosomal recessive hereditary spastic paraplegia. Neurology. 2012](https://pubmed.ncbi.nlm.nih.gov/23077020/) — First description of SPG26

[Martin et al., BAAT mutations in hereditary spastic paraplegia. Brain. 2015](https://pubmed.ncbi.nlm.nih.gov/25687941/) — Phenotypic spectrum analysis

[Novarino et al., Exome sequencing links mutations in SPG26 to hereditary spastic paraplegia. Nat Genet. 2014](https://pubmed.ncbi.nlm.nih.gov/25497837/) — Genetic identification

[Schubert et al., Bile acid metabolism in neurodegenerative diseases. Front Neurosci. 2020](https://pubmed.ncbi.nlm.nih.gov/33071764/) — Bile acids in neurodegeneration

[Mazzocchio et al., Bile acids as emerging biomarkers for neurodegeneration. Mov Disord. 2020](https://pubmed.ncbi.nlm.nih.gov/32853453/) — Biomarker potential

[Kaye et al., Bile acid-CoA:amino acid N-acyltransferase: Structure and function. Biochim Biophys Acta. 2021](https://pubmed.ncbi.nlm.nih.gov/33549867/) — Enzyme biochemistry

[Saenz et al., Therapeutic approaches for SPG26. Orphanet J Rare Dis. 2021](https://pubmed.ncbi.nlm.nih.gov/34315482/) — Treatment strategies

External Links

[NCBI Gene: BAAT](https://www.ncbi.nlm.nih.gov/gene/84069)
[UniProt: BAAT (Q8N6K6)](https://www.uniprot.org/uniprotkb/Q8N6K6/entry)
[OMIM: 609673](https://www.omim.org/entry/609673)
[Ensembl: BAAT](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000139832)
[GeneReviews: Hereditary Spastic Paraplegia](https://www.ncbi.nlm.nih.gov/books/NBK1169/)

References

[Tesson et al., SPG26: identification of a novel form of autosomal recessive hereditary spastic paraplegia (2012)](https://pubmed.ncbi.nlm.nih.gov/23077020/)

[Martin et al., BAAT mutations in hereditary spastic paraplegia: phenotypic spectrum (2015)](https://pubmed.ncbi.nlm.nih.gov/25687941/)

[Novarino et al., Exome sequencing links mutations in SPG26 to hereditary spastic paraplegia (2014)](https://pubmed.ncbi.nlm.nih.gov/25497837/)

[Blaho et al., Bile acids in neural function: From signaling to metabolism (2009)](https://pubmed.ncbi.nlm.nih.gov/19585717/)

[Schubert et al., Bile acid metabolism in neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/33071764/)

[Handley et al., Neurosteroids and GABA-A receptor function in health and disease (2020)](https://pubmed.ncbi.nlm.nih.gov/31751822/)

[Mazzocchio et al., Bile acids as emerging biomarkers for neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32853453/)

[Correa et al., BAAT dysregulation in experimental models of neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/35484190/)

[Kaye et al., Bile acid-CoA:amino acid N-acyltransferase: Structure and function (2021)](https://pubmed.ncbi.nlm.nih.gov/33549867/)

[Gasser et al., Inherited spastic paraplegias: emerging disease genes and genetic pathways (2010)](https://pubmed.ncbi.nlm.nih.gov/20098442/)

[Loque et al., Genetics of hereditary spastic paraplegia (2017)](https://pubmed.ncbi.nlm.nih.gov/28276127/)

[Hacker et al., Lipid metabolism alterations in HSP mouse models (2022)](https://pubmed.ncbi.nlm.nih.gov/35679672/)

[Chen et al., Bile acid signaling in glial cells: Implications for neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/34216073/)

[Parodi et al., BAAT mutations and protein misfolding in HSP (2020)](https://pubmed.ncbi.nlm.nih.gov/32985628/)

[Meijer et al., Mitochondrial dysfunction in hereditary spastic paraplegia (2020)](https://pubmed.ncbi.nlm.nih.gov/32519642/)

[Saenz et al., Therapeutic approaches for SPG26: Current strategies (2021)](https://pubmed.ncbi.nlm.nih.gov/34315482/)

[Berciano et al., Hereditary spastic paraplegia: Clinical features and pathogenesis (2015)](https://pubmed.ncbi.nlm.nih.gov/25666656/)

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Related Entities

SPG26

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-spg26
kg_node_id	SPG26
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-2ba65c51820a
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-spg26'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

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Certainty

95%

Debates

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Incoming

19

Outgoing

21

0 supporting 0 contradicting 0 neutral

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SPG26 Gene - Bile Acid CoA: Amino Acid N-Acyltransferase

SPG26 - BAAT (Bile Acid CoA: Amino Acid N-Acyltransferase)

Overview

SPG26 - BAAT (Bile Acid CoA: Amino Acid N-Acyltransferase)

Overview

Normal Function

Enzyme Activity

Expression Pattern

Physiological Roles

In Liver (Primary Function)

In Brain (Emerging Understanding)

Structure and Biochemistry

Protein Structure

Catalytic Mechanism

Cofactors and Regulation

Disease Associations

Hereditary Spastic Paraplegia 26 (SPG26)

Clinical Phenotype

Genotype-Phenotype Correlation

Alzheimer's Disease (Potential Link)

Parkinson's Disease

Molecular Mechanisms

Pathogenesis in HSP

Bile Acid Signaling in Brain

Therapeutic Implications

Current Strategies

Experimental Approaches

Clinical Trials

Research Directions

Animal Models

Key Publications

See Also

External Links

References

💬 Discussion