| SPG26 Gene | |
|---|---|
| Official Symbol | BAAT |
| Previous Symbol | SPG26 |
| Full Name | Bile Acid CoA: Amino Acid N-Acyltransferase |
| Chromosomal Location | 12q21.31 |
| NCBI Gene ID | [84069](https://www.ncbi.nlm.nih.gov/gene/84069) |
| OMIM | [609673](https://www.omim.org/entry/609673) |
| UniProt ID | [Q8N6K6](https://www.uniprot.org/uniprotkb/Q8N6K6/entry) |
| Protein Category | Enzyme - Aminotransferase |
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 [1]. 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 [2]. The identification of BAAT as the causative gene has opened new avenues for understanding how lipid metabolism intersects with neurodevelopment and neurodegeneration.
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 [3]. This enzymatic reaction occurs in the liver peroxisomes and requires:
The reaction follows this scheme:
Bile Acid-CoA + Amino Acid → Bile Acid-Amino Acid + CoA
BAAT is expressed in multiple tissues with varying levels:
Within the brain, BAAT expression has been detected in:
BAAT is a 524-amino acid enzyme with distinct functional domains:
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.
BAAT uses a ping-pong bi-bi mechanism:
| 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 |
Patients with SPG26 due to BAAT mutations present with:
Motor symptoms:
Cognitive symptoms:
Neurological features:
Over 30 pathogenic variants have been identified in BAAT, including:
Compounds heterozygous mutations often lead to milder phenotypes, while homozygous null alleles cause more severe disease.
Emerging evidence suggests BAAT dysregulation may contribute to AD pathogenesis:
BAAT may play protective roles in PD:
The mechanisms by which BAAT mutations cause HSP include:
Loss of enzymatic function:
Metabolic dysregulation:
Cellular stress:
Neurosteroid dysregulation:
Bile acids serve as signaling molecules through:
| 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 |
Several trials are investigating:
Key areas for future research include:
Several model systems have been used to study BAAT:
SPG26: identification of a novel form of autosomal recessive hereditary spastic paraplegia. Neurology. 2012. ↩︎
BAAT mutations in hereditary spastic paraplegia: phenotypic spectrum. Brain. 2015. ↩︎
Bile acid-CoA:amino acid N-acyltransferase: Structure and function. Biochim Biophys Acta Proteins Proteom. 2021. ↩︎
Bile acids as emerging biomarkers for neurodegeneration. Mov Disord. 2020. ↩︎
Bile acid metabolism in neurodegenerative diseases. Front Neurosci. 2020. ↩︎