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MTTP
microsomal triglyceride transfer protein
The MTTP gene provides instructions for the microsomal triglyceride transfer protein, which is essential for producing lipoproteins that transport fats and fat-soluble vitamins throughout the body. The MTTP gene encodes the microsomal triglyceride transfer protein, a key component in the assembly of beta-lipoproteins.
MTTP is located on the long (q) arm of chromosome 4, at band 4q23. Arm ratio per GRCh38 - banding schematic.
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Overview
The MTTP gene, also known as microsomal triglyceride transfer protein, plays a critical role in human metabolism. It provides the genetic blueprint for a protein integral to the formation of lipoproteins, which are responsible for transporting fats, cholesterol, and fat-soluble vitamins throughout the body [PMID:10515609].
Proper function of the MTTP gene is essential for nutrient absorption in the intestine and for delivering necessary lipids to tissues from the liver. Disruptions in this gene's activity can have significant health implications, particularly affecting the body's ability to process and utilise dietary fats and essential vitamins.
What the gene does
The protein encoded by the MTTP gene, microsomal triglyceride transfer protein (MTP), is instrumental in the assembly of beta-lipoproteins. These complex molecules are composed of proteins, cholesterol, phospholipids, and triglycerides.
In the intestine, MTP is crucial for forming chylomicrons. Chylomicrons are lipoproteins that carry dietary fats and cholesterol from the digestive tract into the bloodstream following a meal. They are also vital for the absorption of fat-soluble vitamins, including vitamins A, E, and K. In the liver, MTP facilitates the production of very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). These lipoproteins then transport fats, cholesterol, and fat-soluble vitamins from the liver to various tissues throughout the body, ensuring cells and tissues receive sufficient levels for normal growth, development, and maintenance [PMID:10515609].
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Chromosome location
The MTTP gene is situated on the long arm of chromosome 4 at position 4q23. This genomic location is where the genetic instructions for the microsomal triglyceride transfer protein are found.
Protein structure
The microsomal triglyceride transfer protein, encoded by the MTTP gene, has a length of 894 amino acids. A prominent feature of its structure is the Vitellogenin domain, which spans amino acids 28 to 659. This domain is crucial for the protein's lipid-binding and transfer capabilities.
Key variants
Over 60 different pathogenic variants within the MTTP gene have been identified. These genetic alterations can lead to the production of a microsomal triglyceride transfer protein that has reduced or absent function. Such variants can significantly impair the protein's ability to facilitate lipid transport.
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.1026_1030dup | p.Ile344fs | Pathogenic | ★★☆☆ | not provided |
c.1197del | p.Phe399fs | Pathogenic/Likely pathogenic | ★★☆☆ | Abetalipoproteinaemia |
c.1769+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Abetalipoproteinaemia |
c.2031del | p.Thr678fs | Pathogenic/Likely pathogenic | ★★☆☆ | Abetalipoproteinaemia |
c.2228T>A | p.Leu743Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Abetalipoproteinaemia |
c.2342+1G>A | - | Pathogenic | ★★☆☆ | Abetalipoproteinaemia |
c.2351_2352del | p.Val784fs | Pathogenic/Likely pathogenic | ★★☆☆ | Abetalipoproteinaemia |
c.399dup | p.Glu134fs | Pathogenic/Likely pathogenic | ★★☆☆ | MTTP-related disorder |
c.415C>T | p.Gln139Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Abetalipoproteinaemia |
c.672del | p.Asp224fs | Pathogenic/Likely pathogenic | ★★☆☆ | Abetalipoproteinaemia |
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
Variants in the MTTP gene are primarily associated with Abetalipoproteinaemia, a rare inherited disorder. This condition significantly impairs the normal absorption of dietary fats and fat-soluble vitamins. The primary organ systems affected typically include the gastrointestinal system, eyes, nervous system, and blood [PMID:10515609].
UK clinical status
The MTTP gene is currently reviewed on several NHS England National Genomic Test Directory panels. It has a 'green' status for conditions including Ataxia and cerebellar anomalies - childhood onset, Hereditary ataxia, Hereditary ataxia, adult onset, Hereditary neuropathy, Hereditary neuropathy or pain disorder (R78), Intestinal failure or congenital diarrhoea (R331), Likely inborn error of metabolism (R98), Retinal disorders (R32), and Undiagnosed metabolic disorders, indicating its established clinical relevance for these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the MTTP gene?
The MTTP gene provides instructions for the microsomal triglyceride transfer protein, which is essential for assembling lipoproteins. These lipoproteins are critical for transporting dietary fats, cholesterol, and fat-soluble vitamins throughout the body.
What health condition is linked to MTTP gene variants?
Pathogenic variants in the MTTP gene are primarily associated with Abetalipoproteinaemia. This condition impairs the body's ability to absorb fats and fat-soluble vitamins, affecting multiple organ systems.
Why are fat-soluble vitamins important for MTTP function?
The microsomal triglyceride transfer protein helps form chylomicrons in the intestine, which are necessary for the absorption of fat-soluble vitamins such as A, E, and K. Without proper MTTP function, the absorption of these crucial vitamins is compromised.
References
- Walsh MT, Hussain MM. Targeting microsomal triglyceride transfer protein and lipoprotein assembly to treat homozygous familial hypercholesterolemia. Critical reviews in clinical laboratory sciences. 2017. PMID: 27690713
- Gündüz M, Özaydın E, Atar MB. Microsomal triglyceride transfer protein gene mutations in Turkish children: A novel mutation and clinical follow up. Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology. 2016. PMID: 27160094
- Walsh MT, Di Leo E, Okur I. Structure-function analyses of microsomal triglyceride transfer protein missense mutations in abetalipoproteinemia and hypobetalipoproteinemia subjects. Biochimica et biophysica acta. 2016. PMID: 27487388
- Benayoun L, Granot E, Rizel L. Abetalipoproteinemia in Israel: evidence for a founder mutation in the Ashkenazi Jewish population and a contiguous gene deletion in an Arab patient. Molecular genetics and metabolism. 2007. PMID: 17275380
- Swift LL, Kakkad B, Boone C. Microsomal triglyceride transfer protein expression in adipocytes: a new component in fat metabolism. FEBS letters. 2005. PMID: 15922333
- Hooper AJ, van Bockxmeer FM, Burnett JR. Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism. Critical reviews in clinical laboratory sciences. 2005. PMID: 16390683
- Hussain MM, Iqbal J, Anwar K. Microsomal triglyceride transfer protein: a multifunctional protein. Frontiers in bioscience : a journal and virtual library. 2003. PMID: 12700048