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DGAT1
diacylglycerol O-acyltransferase 1
DGAT1 is located on the long (q) arm of chromosome 8, at band 8q24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
DGAT1 encodes diacylglycerol O-acyltransferase 1, a membrane-bound enzyme that plays a central role in lipid metabolism. This protein catalyses the final committed step in triglyceride synthesis by attaching a fatty acid to diacylglycerol, forming triacylglycerol. DGAT1 is particularly abundant in the small intestine, where it enables enterocytes to package dietary fats into chylomicrons for absorption into the bloodstream. Pathogenic variants in DGAT1 follow an autosomal recessive inheritance pattern and are associated with congenital diarrhoea and protein-losing enteropathy, a severe disorder characterised by chronic diarrhoea, failure to thrive, and loss of serum proteins through the intestinal lining from early infancy.
What the gene does
The DGAT1 protein functions as an acyltransferase enzyme, catalysing the esterification of diacylglycerol with a long-chain fatty acyl-CoA to produce triacylglycerol. This reaction represents the sole committed step in the glycerol phosphate pathway of triglyceride biosynthesis. DGAT1 localises to the endoplasmic reticulum membrane, where it works alongside other enzymes in the lipid synthesis pathway to convert dietary lipids into neutral storage forms.
In the intestinal epithelium, DGAT1 is essential for the re-esterification of absorbed fatty acids into triglycerides, which are then incorporated into chylomicron particles for transport through the lymphatic system. Beyond the gut, DGAT1 contributes to triglyceride synthesis in adipose tissue, liver, and mammary glands. The enzyme exhibits substrate specificity for diacylglycerol species and displays distinct tissue-specific expression patterns that reflect its physiological roles in energy storage and lipid homeostasis.
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Chromosome location
DGAT1 is located on chromosome 8 at position q24.3, within the long arm of the chromosome. This chromosomal region spans several megabases and contains multiple genes involved in metabolic regulation. The DGAT1 gene comprises multiple exons that encode a 488-amino-acid protein. The genomic structure allows for alternative splicing events, although the predominant transcript produces the full-length functional enzyme.
Protein structure
The DGAT1 protein comprises 488 amino acids organised into several functionally important regions. The N-terminal portion (amino acids 1-91) is involved in homomerisation, enabling the protein to form functional oligomers within the endoplasmic reticulum membrane. This region overlaps with a disordered segment (amino acids 1-57) that likely provides structural flexibility.
The core catalytic region adopts an MBOAT fold (amino acids 131-488), characteristic of the membrane-bound O-acyltransferase superfamily. This domain contains multiple membrane-spanning segments with intervening loops. Extracellular loop 1 (amino acids 119-130) and two intracellular loops (IL1 at amino acids 224-276 and IL2 at amino acids 354-399) facilitate substrate recognition and catalysis. Within IL2 lies the conserved FYXDWWN motif (amino acids 360-366), essential for acyltransferase activity. An amphipathic helix (amino acids 380-394) near the C-terminus contributes to membrane association and protein stability.
Key variants
Pathogenic variants in DGAT1 typically result in loss of enzyme function, abolishing the protein's ability to catalyse triglyceride synthesis. Most disease-causing changes are predicted to severely disrupt protein folding, active-site geometry, or membrane topology. Because DGAT1-related conditions follow autosomal recessive inheritance, affected individuals carry pathogenic variants on both gene copies, whilst carriers with one variant generally remain asymptomatic.
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.1183C>T | p.Arg395Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital diarrhea 7 with exudative enteropathy |
c.1190del | p.Gly397fs | Pathogenic | ★★☆☆ | Congenital diarrhea 7 with exudative enteropathy |
c.355C>T | p.Gln119Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital diarrhea 7 with exudative enteropathy |
c.629_631del | p.Ser210del | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital diarrhea 7 with exudative enteropathy |
c.751+2T>C | - | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.838C>T | p.Arg280Ter | Pathogenic | ★★☆☆ | Congenital diarrhea 7 with exudative enteropathy |
c.210_231dup | p.Ser78fs | Pathogenic | ★☆☆☆ | not provided |
c.367_368del | p.Leu123fs | Pathogenic | ★☆☆☆ | not provided |
c.401dup | p.Cys135fs | Pathogenic | ★☆☆☆ | not provided |
c.796_809del | p.Asn266fs | Pathogenic | ★☆☆☆ | Congenital diarrhea 7 with exudative enteropathy |
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
Biallelic pathogenic variants in DGAT1 cause congenital diarrhoea and protein-losing enteropathy, a rare disorder presenting in the neonatal period or early infancy. Affected individuals experience chronic diarrhoea with fat malabsorption, leading to failure to thrive, hypoalbuminaemia, and oedema. The condition arises because enterocytes cannot properly re-esterify absorbed fatty acids into triglycerides for chylomicron assembly, resulting in defective lipid transport and intestinal dysfunction. Clinical management typically involves dietary modification with medium-chain triglycerides, which bypass the need for DGAT1 activity, alongside nutritional support to address protein and micronutrient deficiencies.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DGAT1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
DGAT1 appears on the NHS Genomic Medicine Service PanelApp as part of the Intestinal failure or congenital diarrhoea panel (version R331), where it holds green classification status. This designation indicates strong evidence supporting DGAT1's role in congenital diarrhoeal disorders, and the gene is evaluated in the context of inherited causes of chronic intestinal dysfunction requiring specialist assessment and management.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the DGAT1 gene do?
DGAT1 encodes an enzyme that catalyses the final step in triglyceride synthesis, converting diacylglycerol and fatty acids into triacylglycerol. This process is particularly important in the small intestine, where it enables the absorption of dietary fats.
How is DGAT1-related congenital diarrhoea inherited?
DGAT1-related disorders follow an autosomal recessive inheritance pattern. An affected individual inherits one pathogenic variant from each parent, who are typically unaffected carriers.
Can DGAT1 variants affect nutrient absorption?
Yes. Loss of DGAT1 function severely impairs fat absorption in the intestine, leading to chronic diarrhoea, malnutrition, and protein loss. Management often includes dietary adjustments such as medium-chain triglycerides, which do not require DGAT1 for absorption.