Molecular characterization of Tunisian families with abetalipoproteinemia and identification of a novel mutation in MTTP gene

Abstract

BackgroundAbetalipoproteinemia (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.MethodsIntestinal biopsies were performed and The MTTP gene was amplified by Polymerase chain reaction then directly sequenced in patients presenting chronic diarrhea and retarded growth.ResultsFirst 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.ConclusionsWe discovered a novel mutation in MTTP gene and we confirmed the diagnosis of abetalipoproteinemia in new Tunisian families.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8134027928652779.

Abetalipoproteinemia: Three Case Reports, a Novel Microsomal Triglyceride Transfer Protein Gene Mutation and a Literature Review

“…Summary of the clinical characteristics and the results of laboratory tests of the three patients with ABL are shown in Tables 1 and 2. Discussion ABL is a rare autosomal recessive disorder caused by mutations in the MTP encoding gene [1,6,[8][9][10]13]. Many mutations were identified in the MTTP gene in patients with ABL [5].…”

“…A novel non conservative missense mutation (H529R) was responsible for ABL phenotype in a six-month-old Iranian female infant which was born to consanguineous parents [3]. Other mutations were also reported to cause ABL like c.1586 A>G-H529R [3], p.Leu435His, c.619-5_619-2del [5], c.1783C>T, 59del17, c.582 C>A [9], c.1389, c.923 G>A, c.2611delC [10], and c.2076-39_2303+52del319 [14]. Mild clinical phenotypes of ABL are caused by some missense mutations of MTP gene that reduce but do not completely stop the gene activities [9].…”

“…MTP deficiency prevent proper lipidation of Apo B and leads to rapid intracellular degradation [3,9]. Subsequently, plasma Apo B containing lipoproteins, such as VLDL and LDL, are undetectable in the plasma [3,9,10,12,15]. Low level of Apo B containing lipoproteins that transport most of the cholesterol results in low plasma cholesterol concentration [6,8,9,16].…”

“…The prevalence is ranging between less than 1 in 100,000 [2,6] and less than 1 in one million [3]. It is caused by mutations in the microsomal triglyceride transfer protein (MTP) gene [2,9,10]. MTP is the protein responsible for the transfer of triglycerides (TG), cholesteryl ester and phospholipids on to the apolipoprotein B (Apo B) [1].…”

“…Apo B promotes the secretion of chylomicrons and very low density lipoproteins (VLDL) from the enterocytes and hepatocytes [1]. Deficiency of the MTP genes results in absence of apo B-containing lipoproteins such as low density lipoproteins (LDL), VLDL and chylomicrons [2][3][4][9][10][11].…”