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Background Abetalipoproteinemia (ABL) and Homozygous Familial Hypobetalipoproteinemia (Ho-FHBL) are rare monogenic diseases characterised by very low plasma levels of cholesterol and triglyceride and the absence or a great reduction of apolipoprotein B (apoB)-containing lipoproteins. ABL results from mutations in the MTP gene; Ho-FHBL may be due to mutations in the APOB gene. Methods We sequenced MTP and APOB genes in three Tunisian children, born from consanguineous marriage, with very low levels of plasma apoB-containing lipoproteins associated with severe intestinal fat malabsorption. Results Two of them were found to be homozygous for two novel mutations in intron 5 (c.619-3T > G) and in exon 8 (c.923 G > A) of the MTP gene, respectively. The c.619-3T > G substitution caused the formation of an abnormal mRNA devoid of exon 6, predicted to encode a truncated MTP of 233 amino acids. The c.923 G > A is a nonsense mutation resulting in a truncated MTP protein (p.W308X). The third patient was homozygous for a novel nucleotide deletion (c.2172delT) in exon 15 of APOB gene resulting in the formation of a truncated apoB of 706 amino acids (apoB-15.56). Conclusions These mutations are expected to abolish the apoB lipidation and the assembly of apoB-containing lipoproteins in both liver and intestine.

Niemann–Pick C, the autosomal recessive neuro-visceral disease resulting from a failure of cholesterol trafficking within the endosomal–lysosomal pathway, is due to mutations in NPC1 or NPC2 genes. We characterized 34 unrelated patients including 32 patients with mutations in NPC1 gene and two patients in NPC2 gene. Overall, 33 distinct genotypes were encountered. Among the 21 unpublished NPC1 alleles, 15 were due to point mutations resulting in 13 codon replacements (p.C100S, p.P237L, p.R389L, p.L472H, p.Y634C, p.S636F, p.V780G, p.Q921P, p.Y1019C, p.R1077Q, p.L1102F, p.A1187V, and p.L1191F) and in two premature stop codons (p.R934X and p.Q447X); a new mutant carried two in cis mutations, p.[L648H;M1142T] and four other NPC1 alleles were small deletions/insertions leading both to frame shifts and premature protein truncations (p.C31WfsX26, p.F284LfsX26, p.E1188fsX54, and p.T1205NfsX53). Finally, the new intronic c.464-2A>C change at the 3′ acceptor splice site of intron 4 affected NPC1 messenger RNA processing. We also found a new NPC2 mutant caused by a change of the first codon (p.M1L). The novel missense mutations were further investigated by two bioinformatics approaches. Panther proein classification system computationally predicted the detrimental effect of all new missense mutations occurring at evolutionary conserved positions. The other bioinformatics approach was based on prediction of structural alterations induced by missense mutations on the NPC1 atomic models. The in silico analysis predicted protein malfunctioning and/or local folding alteration for most missense mutations. Moreover, the effects of the missense mutations (p.Y634C, p.S636F, p.L648H, and p.V780G) affecting the sterol-sensing domain (SSD) were evaluated by docking simulation between the atomic coordinates of SSD model and cholesterol.