UniProtKB/Swiss-Prot P55157: Variant p.Arg540His

Microsomal triglyceride transfer protein large subunit
Gene: MTTP
Chromosomal location: 4q24
Variant information

Variant position:  540
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

Residue change:  From Arginine (R) to Histidine (H) at position 540 (R540H, p.Arg540His).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from large size and basic (R) to medium size and polar (H)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  0
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Abetalipoproteinemia (ABL) [MIM:200100]: An autosomal recessive disorder of lipoprotein metabolism. Affected individuals produce virtually no circulating apolipoprotein B-containing lipoproteins (chylomicrons, VLDL, LDL, lipoprotein(A)). Malabsorption of the antioxidant vitamin E occurs, leading to spinocerebellar and retinal degeneration. {ECO:0000269|PubMed:10679949, ECO:0000269|PubMed:10946006, ECO:0000269|PubMed:22236406, ECO:0000269|PubMed:23475612, ECO:0000269|PubMed:25108285, ECO:0000269|PubMed:26224785, ECO:0000269|PubMed:8939939}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In ABL; no loss on localization to the endoplasmic reticulum; reduces interaction with P4HB/PDI; inhibits phospholipid or triglyceride transfer activity; inhibits apolipoprotein B secretion.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  540
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  894
The length of the canonical sequence.

Location on the sequence:   VKKTLNRIYHQNRKVHEKTV  R TAAAAIILNNNPSYMDVKNI
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         VKKTLNRIYHQNRKVHEKTVRTAAAAIILNNNPSYMDVKNI

Mouse                         VKKTLNRIYHQNRKVHEKTVRTTAAAVILK-NPSYMDVKNI

Pig                           VKKTMNRIYHQTRKVHEKTVRTTAAAVILNNNPSYMEVKNI

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 19 – 894 Microsomal triglyceride transfer protein large subunit
Domain 28 – 659 Vitellogenin
Alternative sequence 152 – 894 Missing. In isoform 2.
Mutagenesis 528 – 528 Y -> F. Does not inhibit triglyceride transfer activity.
Mutagenesis 528 – 528 Y -> K. Inhibits triglyceride transfer activity.
Mutagenesis 540 – 540 R -> A. Strongly reduces triglyceride transfer activity.
Mutagenesis 540 – 540 R -> K. Does not inhibit triglyceride transfer activity and apolipoprotein B secretion.


Literature citations

Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia.
Khatun I.; Walsh M.T.; Hussain M.M.;
J. Lipid Res. 54:1541-1549(2013)
Cited for: FUNCTION; INTERACTION WITH P4HB; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANTS ABL HIS-540; ILE-590; GLU-746 AND TYR-780; CHARACTERIZATION OF VARIANT ALA-384;

A novel abetalipoproteinemia genotype. Identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase.
Rehberg E.F.; Samson-Bouma M.-E.; Kienzle B.; Blinderman L.; Jamil H.; Wetterau J.R.; Aggerbeck L.P.; Gordon D.A.;
J. Biol. Chem. 271:29945-29952(1996)
Cited for: VARIANT ABL HIS-540; VARIANTS GLN-297 AND ALA-384; CHARACTERIZATION VARIANT ABL HIS-540; CHARACTERIZATION VARIANTS GLN-297 AND ALA-384; MUTAGENESIS OF ARG-540; FUNCTION; INVOLVEMENT IN ABL;

Microsomal triglyceride transfer protein (MTP) gene mutations in Canadian subjects with abetalipoproteinemia.
Wang J.; Hegele R.A.;
Hum. Mutat. 15:294-295(2000)
Cited for: VARIANTS ABL HIS-540; ILE-590 AND GLU-746;

Novel missense MTTP gene mutations causing abetalipoproteinemia.
Miller S.A.; Burnett J.R.; Leonis M.A.; McKnight C.J.; van Bockxmeer F.M.; Hooper A.J.;
Biochim. Biophys. Acta 1842:1548-1554(2014)
Cited for: VARIANTS ABL ARG-264; HIS-528; CYS-540 AND SER-649; CHARACTERIZATION OF VARIANTS ABL ARG-264; HIS-528; CYS-540; HIS-540 AND SER-649; FUNCTION; INTERACTION WITH APOB AND P4HB; MUTAGENESIS OF TYR-528;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.