title: Homozygous familial hypobetalipoproteinemia: two novel mutations in the splicing sites of apolipoprotein B gene and review of the literature.
abstract: OBJECTIVE
  Familial hypobetalipoproteinemia (FHBL) is autosomal codominant disorder of lipoprotein metabolism characterized by low plasma levels of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5(th) percentile of the distribution in the population. Patients with the clinical diagnosis of homozygous FHBL (Ho-FHBL) are extremely rare and few patients have been characterized at the molecular level. Here we report the medical history and the molecular characterization of one paediatric patient with clinical features of Ho-FHBL.
  
  
  METHODS
  A one month old infant with failure to thrive, severe hypocholesterolemia and acanthocytosis was clinically and genetically characterized. Molecular characterization of the proband and her parents was performed by direct sequencing of the APOB gene and functional role of the identified mutations was assessed by the minigene methodology.
  
  
  RESULTS
  The proband was found carrying two novel splicing mutations of the APOB gene (c.3696+1G > C and c.3697-1G > A). CHOK1H8 cells expressing minigenes harbouring the mutations showed that these two mutations were associated with the retention of intron 23 and skipping of exon 24, resulting in two truncated apoB fragments of approximate size of 26-28 % of ApoB-100 and the total absence of apoB.
  
  
  CONCLUSIONS
  We describe the first case of Ho-FHBL due to two splicing mutations affecting both the donor and the acceptor splice sites of the same intron of the APOB gene occurring in the same patient. The clinical management of the proband is discussed and a review of the clinical and genetic features of the published Ho-FHBL cases is reported.
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), Università degli Studi di Palermo, Italy.
authors.forename: Angelo B
authors.initials: AB
authors.lastname: Cefalù
authors.affiliation: Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Giuseppe D
authors.initials: GD
authors.lastname: Norata
authors.affiliation: Department of Paediatrics, Melloni Hospital, Milano, Italy.
authors.forename: Daniele G
authors.initials: DG
authors.lastname: Ghiglioni
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), Università degli Studi di Palermo, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Noto
authors.affiliation: Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Uboldi
authors.affiliation: Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Garlaschelli
authors.affiliation: Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Baragetti
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), Università degli Studi di Palermo, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Spina
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), Università degli Studi di Palermo, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Valenti
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi di Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pederiva
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi di Milano, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Riva
authors.affiliation: Department of Paediatrics, Melloni Hospital, Milano, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Department of Paediatrics, Melloni Hospital, Milano, Italy.
authors.forename: Alexa
authors.initials: A
authors.lastname: Zoja
authors.affiliation: Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy; IRCCS Multimedica, Milano, Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Grigore
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), Università degli Studi di Palermo, Italy. Electronic address: maurizio.averna@unipa.it.
authors.forename: Maurizio R
authors.initials: MR
authors.lastname: Averna
authors.affiliation: Department of Pharmacology and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy; IRCCS Multimedica, Milano, Italy. Electronic address: alberico.catapano@unimi.it.
authors.forename: Alberico L
authors.initials: AL
authors.lastname: Catapano
mesh_terms: D000012:Abetalipoproteinemia / Q000235:genetics; D000328:Adult; D017398:Alternative Splicing; D053299:Apolipoprotein B-100 / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004252:DNA Mutational Analysis; D005260:Female; D006720:Homozygote; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000175:diagnosis* / Q000235:genetics*; D007223:Infant; D007438:Introns; D008297:Male; D009154:Mutation
chemical_list: C569471:APOB protein, human; D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; D002784:Cholesterol
keywords: Acanthocytosis; Apolipoprotein B; Homozygous familial hypobetalipoproteinemia