Molecular characterization of Tunisian families with abetalipoproteinemia and identification of a novel mutation in MTTP gene
© Najah et al.; licensee BioMed Central Ltd. 2013
Received: 6 December 2012
Accepted: 10 January 2013
Published: 4 April 2013
Abetalipoproteinemia (ABL; OMIM 200100) is a rare monogenic disorder of lipid metabolism characterized by reduced plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and almost complete absence of apolipoprotein B (apoB). ABL results from genetic deficiency in microsomal triglyceride transfer protein (MTP; OMIM 157147). In the present study we investigated two unrelated Tunisian patients, born from consanguineous marriages, with severe deficiency of plasma low-density lipoprotein (LDL) and apo B.
Intestinal biopsies were performed and The MTTP gene was amplified by Polymerase chain reaction then directly sequenced in patients presenting chronic diarrhea and retarded growth.
First proband was homozygous for a novel nucleotide deletion (c. 2611delC) involving the exon 18 of MTTP gene predicted to cause a non functional protein of 898 amino acids (p.H871I fsX29). Second proband was homozygous for a nonsense mutation in exon 8 (c.923 G > A) predicted to cause a truncated protein of 307 amino acids (p.W308X), previously reported in ABL patients.
We discovered a novel mutation in MTTP gene and we confirmed the diagnosis of abetalipoproteinemia in new Tunisian families.
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KeywordsAbetalipoproteinemia Tunisian children Mutations MTTP gene
ABL is a rare autosomal recessive metabolic disorder characterized by very low levels of total cholesterol (TC), low density lipoprotein- cholesterol (LDL-C) and almost the complete absence of apolipoprotein B-containing lipoproteins . Patients with ABL have severe fat malabsorption, retarded growth, lipid accumulation in hepatocytes and enterocytes, and peripheral blood acanthocytosis essentially in early childhood, and later develop a retinitis pigmentosa and neuropathy due to fat soluble vitamins deficiency specifically vitamin E. Other manifestations of ABL include also hepatic steatosis and hepatomegaly . Heterozygotes ABL patients usually have normal plasma levels of TC and LDL-C .
ABL is due to mutations in the MTTP gene encoding for the microsomal triglyceride transfer protein (MTP) a protein of 97-kDa, containing 894 amino acids, that forms an heterodimer with the protein disulfide isomerase (PDI). MTP protein is essentially expressed in endoplasmic reticulum of hepatocytes and enterocytes and plays a key role on the assembly and secretion of apo B-containing lipoproteins in both liver and intestine [4–7].
The MTP molecule consists of three structural domains: N-terminal β-barrel (residues 22–297), α-helical (residues 298–603) and C-terminal domains (residues 604–894). The N-terminal β-barrel domain mediates the interaction with the N terminus of apo B; the middle α-helical domain mediates the interaction with both PDI and apo B; and the C-terminal mediates the lipid-binding and transfer catalytic activity of MTP [6, 8, 9].
To our knowledge, more than 50 patients with ABL were described in the literature. Most of MTTP gene mutations result in truncated proteins [10, 11]. Missense mutations have been also reported in atypical cases of ABL and were associated with a milder form of the disease [12–14].
The aim of the present study was to characterize two unrelated Tunisian patients with the clinical manifestations and plasma lipid profile consistant with ABL. They were found to be homozygous for two mutations respectively, one of which is new in MTTP gene.
Clinical data and recruitment of family members
All subjects investigated are living in Tunisia and are of Tunisian ancestry. Informed consent was obtained from all adult subjects, and in the case of children, from their parents. The study was approved by the Ethics Committees of each participating institution. Family members (parents and their child) of the patients were asked to take part in the study.
Patient II.1 (Family E)
Exploration showed that levels of ASAT and ALAT were 169 IU/L (normal values <38 IU/L) and 214 IU/L (normal values <41 IU/L) respectively. A normal level of gammaglutaryl transferase: 16 IU/L and an elevation of alcaline phosphatase (179 IU/L) (normal values 40–150 IU/L) were observed. Calcemia and total protein were normal. Acanthocytosis was revealed on peripheral blood smear. The lipid levels at the time of hospitalization were CT: 1.3 mmol/l, TG: 0.35 mmol/l and HDL-C: 0.9 mmol/l. Values of vitamins were 430 μg/l for vitamine A (normal values 444–945 μg/l), vitamine E (<1 μmol/l) was undetectable (normal values 16–35 μmol/l). The patient was treated by restricting dietary fat and by supplementation of fat soluble vitamin A 25 000 IU daily and vitamin E 500 mg daily during three months. No neurological or ophthalmic abnormalities were found.
Patient II.2 (Family D)
Lipid and lipoprotein analysis
For all family members plasma lipid values were obtained after an overnight fast. Plasma TC, TG and HDL-C concentrations were measured by a standard method using the Synchrom CX7 clinical system (Beckman, Fullerton, CA, USA). LDL-C concentration was calculated using the Friedewald’s Formula. ApoA-I, apoB were measured by immunonephelometry using the IMMAGE immunochemistry system (Beckman, Fullerton, CA, USA).
Following a period of 12 hours fasting, duodenal biopsies were obtained from probands. Tissues were fixed in 10% buffered formalin and embedded in paraffin for routine histology stained with hematoxylin and eosin.
Genomic DNA was isolated from whole blood EDTA samples using the salting-out method . For the family E patient, MTTP gene was amplified and directly sequenced as previously described . In the case of family D, The promoter and all exons as well as flanking intronic sequences of the MTTP gene were amplified by polymerase chain reaction (PCR) as previously described , then PCR products were sequenced using BigDyeDeoxy terminator cycle sequencing reagents according to the manufacturer’s instructions and templates were sequenced on an automated ABI-PRISM 310 Genetic Analyzer (Applied Biosystems). Further, the MTTP mutations found in the probands were screened by direct sequencing in all family members available for study.
MTTP mutations were designated according to the Human Genome Variation Society. Nucleotide numbers are derived from MTTP cDNA sequence (GenBank accession no. NM_000253.2), considering the A of first ATG translation initiation codon as nucleotide +1. Amino acid sequence MTP protein are described according to the National Center for Biotechnology Information reference sequence (MTP, GenBank accession no. NP_000244.2).
Plasma lipid and apolipoprotein levels in Family E
Plasma lipid and apolipoprotein levels in Family D
In view of the lipid profile of proband’s parents and because we already described a Tunisian ABL family whith hypocholesteroleima in one of his parents , we assumed that the proband might be affected by ABL. The sequence of MTTP gene showed that the proband was homozygous for (c.923 G > A) mutation in exon 8. The result is a truncated protein of 307 amino acids, as opposed to the 894 amino acids, devoid of function. Proband’s parents were heterozygous and his brother (subject II.1 in Figure 2) present on this study was normal.
ABL is a rare autosomal recessive metabolic disorder characterized by complete absence of plasma apo B-containing lipoproteins that results from mutations in MTTP gene. Patients with ABL may develop severe neurological manifestations if they are not treated [2, 17, 18].
Abetalipoproteinemia is characterized, in term of clinical manifestations, with homozygous Familial Hypobetalipoproteinmia (FHBL; OMIM 107730) and Chylomicron Retention disease (CMRD; OMIM 246700), two other monogenic disorders of lipid metabolism by manifestations such as steatorrhea, retarded growth and chronic diarrhea associated with hypocholesterolemia. Under these conditions the use of the lipid profile of proband’s parents is essential to lead and facilitate the molecular diagnosis of these metabolic disorders: familial hypobetalipoproteinemia is a rare autosomal codominant disorder of lipoprotein metabolism, it results that both parents are expected to have plasma levels of TC, LDL-C and apoB lower than those found in normal subjects [3, 19]. In ABL and CMRD with an autosomal recessive transmission, obligate heterozygotes have almost normal plasma lipoprotein profiles, with some exception and usually normal level of TG in patients homozygous for CMRD [2, 20].
In this paper, we characterize two new Tunisian families with a severe form of hypobetalipoproteinemia. The common clinical features shared by patients were diarrhea, failure to thrive, acanthocytosis and lipid accumulation in enterocytes. The diagnosis of ABL was confirmed in these families and patients were found to be homozygotes for two mutations; one of them, which involves the exon 18, is novel on MTTP gene.
In the case of families E and D, probands presented with a similar lipid profile and very low plasma levels of TC, TG and undetectable LDL-C and apoB. In family E, the lipid values of proband’s parents, were within the normal range (Table. 1). The MTTP gene sequencing showed that proband of family E was homozygous for a novel mutation on MTTP gene (c.2611delC), predicted to result in a protein of 898 amino acids. It is well known that C-terminal domain (residues 604–894) mediate the lipid binding and the transfer catalytic activity of MTP [8, 27]. The abnormal protein is expected to be non functional, since the sequence of the C-terminal domain was changed. It was demonstrated that C-terminal domain is preferentially conserved amongst vertebrates suggesting that this region might be critical for the triacylglycerol transfer activity associated with MTP . The truncated MTP protein resulting from the mutation (p.G865X), involving the exon 18, was suggested to interfere with the association between the 97 kD subunit of MTP and PDI [24, 29]. Other MTP truncations devoid of the C-terminal domain [25, 30] or missense mutations located in this domain [12, 13] have been described in patients with ABL highlighting the functional role of the C-terminal domain.
In family D, we found the third Tunisian patient with (c.923 G > A) mutation in homozygous state. This mutation was found for the first time in two Tunisian affected brothers (unrelated to the patient in the present study) and it leads to a truncated MTP protein of 307 amino acids (p.W308X) devoid of function . The proband’s parents were heterozygous and his brother was normal. Proband’s mother (subject I.1 in Table 2) had low plasma lipid levels suggestive of hypobetalipoproteinemia, even though, the lipid plasma values within the lower limit or low values of TC and apoB were observed in heterozygous subjects for the same mutation (c.923 G > A) in a previous study . This is not surprising as heterozygous ABL (specifically one of the parents) were reported with low plasma TC, LDL-C and apoB in other single families [21–23], and the possibility that human MTP deficiency is inherited in a codominant manner had been also suggested in heterozygous of MTP knockout mice with reduced plasma apoB levels .
The proband’s brother (subject II.1 in Table 2), with normal genotype, had low levels of TC and apoB although he was healthy and had no history of malabsorption or failure to thrive. The biochimical phenotype of family D strongly confirms the existence of a Tunisian specificity associated with monogenic dyslipidemias, since we recently showed a low level of plasma lipids in heterozygous for CMRD  and normal or moderate levels of CT and LDL-C in heterozygous familial hypercholestetolemia (FH) . The lipid profile of proband’s brother (subject II.1 in Table 2) can be attributed either to the low content of fats in the mediterranean diet which characterize Tunisian population  or to the coexistence of other cholesterol-lowering gene(s) associated with hypobetalipoproteinemia in this family. In addition, it has been shown that some polymorphisms in genes related to the metabolism of lipoproteins, have been associated with lipid levels in Tunisian patients affected by other diseases like cardiovascular pathologies . This reflects, in part, the genetic background heterogeneity of the Tunisian population demonstrated in other genetic disorders .
Many mutations in MTTP gene described in literature as cause of ABL were private and related to single families. There was an exception with (p.G865X) mutation which was found in ABL patients from USA and Canada and was also reported in the Ashkenazi Jewish population with a high prevalence and a founder effect [12, 25]. The (419insA) mutation was also associated with ABL in patients of European ancestry [13, 26]. In Tunisian population, four mutations in MTTP gene (c.923 G > A, c.619-3 T > G, c.1236 + 2 T > G and c.2342 + 1 G > A) have been reported as cause of ABL in four single families [10, 36]. In this study, the diagnosis of the mutation (c.923 G > A) in a new Tunisian family is suggestive of a high prevalence of the mutant allele in heterozygote state.
Although, the clinical data available were rather incomplete (especially hepatic exploration), our patients presented the typical hematologic and gastrointestinal features of ABL such as acanthocytosis, diarrhea during infancy and malabsorption with mild anemia (proband II.2 of family D in this paper) which was reported in some cases of ABL [10, 21]. Usually neurological manifestations begin later in life in ABL patients, especially those who have not been given a supplementation of vitamin E . Later supplementation of fat soluble vitamins in patient II.2 (family D) allowed the osteotendinous reflexes reduction. Previous studies showed that early therapy with vitamin E, before the age of 16 months prevents neurologic dysfunction [32, 33]. Elevated Transaminases serum of the proband II.1 (family E) is suggestive of hepatic steatosis which is needed to be confirmed by liver biopsy in this patient. It was reported that hepatic manifestations in ABL cases included hepatomegaly due to hepatic steatosis in association with elevated transaminases [34, 41]. The absence of neurological and opthalmological manifestations in patient II.1 (family E) is consistant with the observation that the diagnosis of ABL should be made in children with malabsorption, acanthocytosis and hypocholesterolemia. Indeed a low-fat diet and fat-soluble vitamins supplementation can prevent later complications .
Five ABL patients have been reported in Tunisian population [10, 36]. In this work we characterize two other unrelated patients affected by this metabolic disorder and we identify a novel mutation in MTTP gene leading to a non functional protein. Although it is a rare disease, abetalipoproteinemia seems to have a high prevalence in Tunisia. Knowledge of MTTP gene mutations allows us to set up a sensitive and specific use of genetic testing for screening carriers in other families.
Chylomicron Retention Disease
High density lipoprotein–cholesterol
Low density lipoprotein–cholesterol
Microsomal triglyceride transfer protein
Microsomal triglyceride transfer protein large subunit gene
Polymerase chain reaction
Protein disulfide isomerase
We are indebted to all family members for their cooperation. This work was supported by grants from the Direction Générale de la Recherche Scientifique et Technique (Tunisia). We thank Prof Rouis M. from l’Université Pierre et Marie Curie, Paris, (France) for his assistance and all member team of Laboratory of Biochemistry and Toxicology of the University Hospital of Monastir.
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