Alternative titles; symbols
HGNC Approved Gene Symbol: MTTP
SNOMEDCT: 190787008; ICD10CM: E78.6;
Cytogenetic location: 4q23 Genomic coordinates (GRCh38): 4:99,564,130-99,623,997 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q23 | Abetalipoproteinemia | 200100 | Autosomal recessive | 3 |
Microsomal triglyceride transfer protein catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces. It is a heterodimer composed of a 55-kD multifunctional protein, protein disulfide isomerase (P4HB; 176790), and a unique large subunit with an apparent molecular weight of 88 kD (Wetterau et al., 1990). MTP was isolated as a soluble protein from the lumen of a microsomal fraction of liver and intestine. (Rehberg et al. (1996) referred to the large subunit as the 97-kD subunit.)
Sharp et al. (1993) isolated and sequenced cDNA encoding the large subunit of MTP. A comparison of the normal sequence with the genomic sequences from 2 abetalipoproteinemic subjects demonstrated a homozygous frameshift mutation in one and a homozygous nonsense mutation in the other.
Nakamuta et al. (1996) cloned and sequenced mouse MTP cDNA. The DNA-deduced amino acid sequence indicated that mouse MTP contains 894 amino acids; the mouse protein showed 93, 86, and 83% sequence identity to the hamster, human, and bovine sequences, respectively. Northern blot analysis indicated that mouse MTP mRNA is expressed at high levels in the small intestine and at substantially lower levels in the liver; it was not detectable in 6 other tissues examined. The authors noted that the C-terminal region of MTP was more highly conserved than the N-terminal region in human, bovine, hamster, and mouse.
The MTP gene has 17 introns (Shoulders et al., 1994).
Shoulders et al. (1994) pointed out that MTP has amino acid sequence homology with lipovitellin, a component of an ancient transport and storage lipoprotein found in egg-laying animals. Lipovitellin is derived by proteolytic cleavage of vitellogenin, which is synthesized in the liver under estrogen control, and serves as a source of lipids and amino acids during embryogenesis. Shoulders et al. (1994) showed the MTP is a member of the vitellogenin gene family.
By PCR analysis of rodent/human somatic cell hybrids followed by fluorescence in situ hybridization, Narcisi et al. (1995) mapped the MTP gene to 4q22-q24. By Southern blots of interspecific backcross panels, Nakamuta et al. (1996) mapped the mouse Mtp gene to distal chromosome 3.
Wetterau et al. (1992) reported that the large subunit of MTP was not detectable in 4 unrelated subjects with abetalipoproteinemia (ABL; 200100), a rare autosomal recessive disease characterized by a defect in assembly or secretion of plasma lipoproteins that contain apolipoprotein B (APOB; 107730).
Abetalipoproteinemia
In a cohort of 8 patients with classic abetalipoproteinemia, Narcisi et al. (1995) identified a mutation of the MTP gene in both alleles of all individuals. Each mutant allele was predicted to encode a truncated form of MTP with a variable number of aberrant amino acids at its C-terminal end. Expression of genetically engineered forms of MTP in COS-1 cells indicated to the authors that the C-terminal portion of MTP is necessary for triglyceride-transfer activity. A deletion of 20 amino acids from the carboxyl terminus of the 894-amino acid protein and a missense mutation of cys878-to-ser both abolished activity.
Heath et al. (1997) described a highly informative CA repeat polymorphism within the MTP gene which can be used for diagnosis, including prenatal diagnosis, in lieu of a mutation search, which can be difficult.
Ohashi et al. (2000) stated that 14 separate mutations in the MTP gene and/or cDNA from patients with abetalipoproteinemia had been described. They identified MTP mutations in all 8 alleles of 2 Japanese and 2 American patients with ABL. These included a second incidence of a missense mutation (157147.0007; see 157147.0005 for the first missense mutation described).
Benayoun et al. (2007) investigated the genetic basis for abetalipoproteinemia in a cohort of Israeli families. In Ashkenazi Jewish patients, Benayoun et al. (2007) identified a conserved haplotype and a common MTP mutation, gly865 to ter (157147.0010), with a carrier frequency of 1:131 in this population. They also reported the first case of abetalipoproteinemia and additional abnormalities in a Muslim Arab patient, due to a homozygous contiguous gene deletion of approximately 481 kb, including MTP and 8 other genes.
Cuchel et al. (2007) reported that inhibition of the microsomal triglyceride transfer protein reduces plasma low density lipoprotein (LDL) cholesterol in homozygous familial hypercholesterolemia (143890). Treatment-related hepatic steatosis was predictable from studies in animals, variable among study subjects, and reversible with discontinuation of the inhibitor. Hegele (2007) suggested that clues to the long-term consequences of inhibition of the microsomal triglyceride transfer protein might be found among patients with abetalipoproteinemia (200100). Cirrhosis has been reported in patients with abetalipoproteinemia (Partin et al., 1974). Fat accumulation within enterocytes and steatorrhea are defining features of abetalipoproteinemia; ileal adenocarcinoma developed in one patient with abetalipoproteinemia who survived for a long period (Al-Shali et al., 2003). Cuchel and Rader (2007) agreed with the suggestions of Hegele (2007).
MTTP Polymorphisms
In a cohort of 716 German men genotyped for the ile128-to-thr polymorphism of the MTP gene (I128T; 157147.0009), Rubin et al. (2006) found that compared to wildtype homozygotes, carriers of the less common thr128 allele had significantly lower postprandial insulin levels, lower diastolic blood pressure, and a lower prevalence of impaired glucose metabolism and type 2 diabetes (125853). In a case-control study of 190 patients with type 2 diabetes and 380 controls, Rubin et al. (2006) observed a significantly lower incidence of type 2 diabetes in individuals with the thr128 genotype; the authors suggested that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type 2 diabetes, and other parameters of the metabolic syndrome.
Although deficiency in MTP causes abetalipoproteinemia, the role of MTP in the assembly and secretion of very low density lipoprotein (VLDL) in the liver was not precisely understood. To this end, Raabe et al. (1999) knocked out the Mtp gene in the mouse. Achieving the objective was thwarted by a lethal embryonic phenotype. Raabe et al. (1999) found, however, that they could produce mice harboring a 'floxed' Mtp allele and then use Cre-mediated recombination to generate liver-specific Mtp knockout mice. Inactivation of the Mtp gene in the liver caused a striking reduction in VLDL triglycerides and large reductions in both VLDL/LDL and high density lipoprotein (HDL) cholesterol levels. Mtp gene inactivation lowered apoB-100 levels in the plasma by more than 95% but reduced plasma apoB-48 levels by only approximately 20%. Histologic studies in liver-specific knockout mice revealed moderate hepatic steatosis. Ultrastructural studies of wildtype mouse liver revealed numerous VLDL-sized lipid-staining particles within membrane-bound compartments of the secretory pathway (endoplasmic reticulum (ER) and Golgi apparatus) and few cytosolic lipid droplets. In contrast, VLDL-sized lipid-staining particles were not observed in MTP-deficient hepatocytes, either in the ER or in the Golgi apparatus, and there were numerous cytosolic fat droplets. Raabe et al. (1999) concluded that MTP is essential for transferring the bulk of triglycerides into the lumen of the ER for VLDL assembly and is required for the secretion of apoB-100 from the liver.
In a 39-year-old female with abetalipoproteinemia (ABL; 200100), the offspring of a consanguineous mating, Sharp et al. (1993) isolated total RNA and reverse transcribed it into first-strand cDNA. The cDNA encoding the large subunit of MTP was amplified by PCR and sequenced directly. Three independent PCR products revealed a cytosine deletion at base 215. The frameshift mutation led to a premature stop codon 21 bases downstream and a predicted translation product of 78 amino acids. The 187-bp exon that encoded the mutation was amplified from the subject's genomic DNA and sequenced directly. A single sequence that contained the frameshift mutation was observed, indicating that both alleles contained the defect, i.e., that the patient was homozygous.
Sharp et al. (1993) constructed a genomic library from the DNA of a 14-year-old abetalipoproteinemic (ABL; 200100) female previously shown to lack MTP (Wetterau et al., 1992) and isolated clones encoding the large subunit of MTP. Sequence analysis revealed a C-to-T mutation corresponding to base 1783 of the cDNA. The mutation changed an arg codon to a premature stop codon. A truncated translation product of 594 amino acids was predicted. The nonsense mutation also eliminated a TaqI restriction endonuclease site. The normal exon encoding base 1783 was digested into 2 fragments by TaqI. DNA from the abetalipoproteinemic subject was not digested at this site, indicating that both alleles contained the defect, i.e., the subject was homozygous.
In sibs with abetalipoproteinemia (ABL; 200100) reported by Talmud et al. (1988), Shoulders et al. (1993) demonstrated homozygosity for a splice mutation in the MTP protein. RT-PCR of mRNA prepared from intestinal biopsies from one of the patients provided starting material. By sequencing genomic and cDNA clones from the patient, Shoulders et al. (1993) demonstrated that the patient's cDNA contained an abnormal 91-bp sequence at the site of an intron/exon splice junction between nucleotides 1867 and 1868 encoding amino acid codon 623. The DNA sequence 3-prime of nucleotide 1867 encoded 31 amino acids before an in-frame stop codon was encountered. No abnormality of the invariant GT and AG intron/exon consensus sequences was found. Sequencing of genomic clones from each parent demonstrated a G-to-A substitution at the +5 position of the 5-prime splice site in 1 allele. All of the patient's cDNA and genomic clones bore an A at this position. Thus, the patient had an exon skip, causing a frameshift and the generation of a premature UAG stop codon at nucleotides 1869-1871 of the cDNA. The G-to-A mutation at the +5 position of a splice donor site was associated with production of 2 mRNA species: one failed to splice the intron containing the mutation, and the other skipped the exon immediately upstream.
In a 29-year-old Japanese male with abetalipoproteinemia (ABL; 200100), Yang et al. (1999) identified a homozygous G-to-A transition at the -1 position of the intron 9 splice acceptor site of the MTP gene. This mutation alters the splicing of the mRNA, resulting in an in-frame deletion of a 36-amino acid sequence encoded by exon 10. Analysis of chromosome 4 using short tandem repeat polymorphic markers revealed that the proband had inherited only maternal alleles in chromosome 4q spanning a 150-cM region; i.e., there was segmental maternal isodisomy 4q21-q35, probably due to mitotic recombination. Nonpaternity was excluded using polymorphic markers from different chromosomes (paternity probability, 0.999). Maternal isodisomy (maternal uniparental disomy 4q) was the basis for homozygosity of the MTP gene mutation in this patient.
In a patient with abetalipoproteinemia (ABL; 200100) in whom Wetterau et al. (1992) could detect no large subunit of MTP, Rehberg et al. (1996) performed sequence analysis of cDNAs from additional intestinal biopsies and showed that the patient was a compound heterozygote for mutations in the MTP gene. One allele contained a perfect in-frame deletion of exon 10 (157147.0005), explaining the lower molecular weight band demonstrated by electrophoresis. Rehberg et al. (1996) found that cDNAs of the second allele contained 3 missense mutations. Transient expression of each mutant showed that only one, arg540 to his (R450H), was nonfunctional based upon its inability to reconstitute apoB secretion in a cell culture system. The other 2 amino acid changes were silent polymorphisms. High level coexpression in a baculovirus system of the wildtype 97-kD subunit or the R540H mutant with human protein disulfide isomerase (176790) showed that the wildtype was capable of forming an active MTP complex while the mutant was not. Analysis of lysates from these cells showed that the arg-to-his conversion interrupted the interaction between the 97-kD subunit and protein disulfide isomerase. Replacement of arg540 with a lysine residue maintained the ability of the large subunit to complex with protein disulfide isomerase and form the active MTP holoprotein. This result indicated that a positively charged amino acid at position 540 in the large subunit is critical for the productive association with protein disulfide isomerase. Rehberg et al. (1996) stated that of the 13 mutant MTP 97-kD subunit alleles described up to that time this was the first encoding a missense mutation.
For discussion of the in-frame deletion of exon 10 in the MTTP gene that was identified in compound heterozygous state in a patient with abetalipoproteinemia (ABL; 200100) by Rehberg et al. (1996), see 157147.0005.
In a 27-year-old Japanese male with abetalipoproteinemia (ABL; 200100) who had no history of steatorrhea or other medical problems but who was found to be extremely hypolipemic during a routine medical exam, Ohashi et al. (2000) identified homozygosity for an asn780-to-tyr (N780Y) missense mutation in the MTP gene. His parents were consanguineous. The patient showed neither neurologic nor ophthalmologic abnormalities; however, acanthocytosis and mild fatty liver were detected.
In a 58-year-old man with abetalipoproteinemia (ABL; 200100), Al-Shali et al. (2003) identified homozygosity for a ser590-to-ile (S590I) mutation in the MTP gene. The patient had a lifelong history of fat malabsorption, but the diagnosis of abetalipoproteinemia was not made until age 52 years, based on absence of apolipoprotein B-containing lipoproteins, acanthocytosis, atypical retinitis pigmentosa, and markedly depressed serum beta-carotene concentration. His presentation was notable not only by survival to the sixth decade of life without specific treatment, but also by the absence of neurologic involvement and by normal serum vitamin E concentration. He subsequently developed adenocarcinoma of the ileum, which required ileal resection.
This variant, formerly titled METABOLIC SYNDROME, PROTECTION AGAINST, has been reclassified as a polymorphism.
Rubin et al. (2006) genotyped a cohort of 716 German men for the functional MTP exon polymorphism ile128-to-thr (I128T) and found that compared to wildtype homozygotes, carriers of the less common thr128 allele had significantly lower postprandial insulin levels, lower diastolic blood pressure, and a lower prevalence of impaired glucose metabolism and type 2 diabetes (125853). Consistent with these findings, in a nested case-control study of 190 incident type 2 diabetes cases and 380 sex- or age-matched controls, Rubin et al. (2006) observed a lower incidence of type 2 diabetes in individuals with the thr128 genotype (p = 0.007). Rubin et al. (2006) suggested that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type 2 diabetes, and other parameters of the metabolic syndrome (see 605552).
Hamosh (2023) noted that the I128T variant was present in 69,405 of 279,940 alleles and in 9,277 homozygotes, for an allele frequency of 0.2479 in the gnomAD database.
In 3 unrelated Ashkenazi Jewish families from Israel with abetalipoproteinemia (ABL; 200100), Benayoun et al. (2007) demonstrated that probands were homozygous for a G-to-T transversion at position 2593 in exon 18 of the MTP gene, resulting in a glycine-to-termination substitution at codon 865 (G865X). This mutation was also found in 3 of 786 Ashkenazi Jewish control chromosomes, thus indicating a carrier frequency of 1 in 131 (0.76; 95% confidence interval 0 to 1.8%) in this population. The carrier frequency suggested an abetalipoproteinemia incidence rate of approximately 1 in 69,000 in this population. G865X was not found among 480 chromosomes from non-Ashkenazi Jews. All chromosomes harboring G865X shared the same haplotype of 2 genetic markers which span 208 kb flanking the mutation.
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