Monogenic
hypobetalipoproteinemias include three disorders:
abetalipoproteinemia (ABL) and
chylomicron retention disease (CMRD) with recessive transmission and
familial hypobetalipoproteinemia (FHBL) with dominant transmission. We investigated three unrelated Tunisian children born from consanguineous marriages, presenting
hypobetalipoproteinemia associated with chronic
diarrhea and retarded growth. Proband HBL-108 had a moderate
hypobetalipoproteinemia, apparently transmitted as dominant trait, suggesting the diagnosis of FHBL. However, she had no mutations in FHBL candidate genes (
APOB, PCSK9 and ANGPTL3). The analysis of
MTTP gene was also negative, whereas SAR1B gene resequencing showed that the patient was homozygous for a novel mutation (c.184G>A), resulting in an amino acid substitution (p.Glu62Lys), located in a conserved region of Sar1b
protein. In the HBL-103 and HBL-148 probands, the severity of
hypobetalipoproteinemia and its recessive transmission suggested the diagnosis of ABL. The
MTTP gene resequencing showed that probands HBL-103 and HBL-148 were homozygous for a
nucleotide substitution in the donor splice site of intron 9 (c.1236+2T>G) and intron 16 (c.2342+1G>A) respectively. Both mutations were predicted in silico to abolish the function of the splice site. In vitro functional assay with splicing mutation reporter
MTTP minigenes showed that the intron 9 mutation caused the skipping of exon 9, while the intron 16 mutation caused a partial retention of this intron in the mature
mRNA. The predicted translation products of these mRNAs are non-functional truncated
proteins. The diagnosis of ABL and CMRD should be considered in children born from consanguineous parents, presenting chronic
diarrhea associated with
hypobetalipoproteinemia.