title: Novel mutations in SAR1B and MTTP genes in Tunisian children with chylomicron retention disease and abetalipoproteinemia.
abstract: 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.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Magnolo
authors.forename: Mohamed
authors.initials: M
authors.lastname: Najah
authors.forename: Tatiana
authors.initials: T
authors.lastname: Fancello
authors.forename: Enza
authors.initials: E
authors.lastname: Di Leo
authors.forename: Elisa
authors.initials: E
authors.lastname: Pinotti
authors.forename: Ines
authors.initials: I
authors.lastname: Brini
authors.forename: Neji M
authors.initials: NM
authors.lastname: Gueddiche
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.forename: Naceur M
authors.initials: NM
authors.lastname: Slimene
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tarugi
mesh_terms: D000012:Abetalipoproteinemia / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics; D001055:Apolipoproteins B / Q000235:genetics; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D008055:Lipids / Q000097:blood; D008286:Malabsorption Syndromes / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D014416:Tunisia; D055815:Young Adult
chemical_list: C479896:ANGPTL3 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D001055:Apolipoproteins B; D002352:Carrier Proteins; D008055:Lipids; C106092:microsomal triglyceride transfer protein; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C513282:SAR1B protein, human; D020559:Monomeric GTP-Binding Proteins