title: Familial hypobetalipoproteinemia in a hospital survey: genetics, metabolism and non-alcoholic fatty liver disease.
abstract: BACKGROUND
  Familial hypobetalipoproteinemia (FHBL) is an autosomal dominant disease characterized by abnormally low levels of apolipoprotein-B (apoB) containing lipoproteins. FHBL is caused by APOB, PCSK9 or ANGPTL3 mutations or is associated with loci located in chromosomes 10 and 3p21. However, other genes should be involved. This study describes the kinetic parameters of the apoB containing lipoproteins and sequence abnormalities of the APOB and PCSK9 genes of FHBL patients identified in a large hospital based survey.
  
  
  METHODS
  Cases with primary or secondary causes of hypobetalipoproteinemia were identified. ApoB kinetics were measured in cases with primary forms in whom truncated forms of apoB were not present in VLDL (n = 4). A primed constant infusion of [(13)C] leucine was administered, VLDL and LDL apoB production and catabolic rates measured by a multicompartmental model and compared to normolipemic controls. In addition, these subjects had an abdominal ultrasound and direct sequencing was carried out for the PCSK9 and apoB genes.
  
  
  RESULTS
  Three individuals had normal apoB production with increased catabolic rate; the remaining had reduced synthetic and catabolic rates. Various polymorphisms, some of them previously unreported (*), in the PCSK9 gene (R46L, A53V, I474V, D480N*, E498K*) and in the apoB gene (N441D*, Y1395C, P2712L, D2285E*, I2286V, T3540S*, T3799M*) were found in the FHBL patients. We found hepatic ultrasound changes of hepatic steatosis in only one of the four probands.
  
  
  CONCLUSIONS
  FHBL without truncated apoB is a heterogeneous disease from a metabolic and a genetic perspective. Hypobetalipoproteinemia is a risk factor but not an obligate cause of steatosis.
authors.affiliation: Departamento de Medicina Interna, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México. cirlos@hotmail.com
authors.forename: Carlos
authors.initials: C
authors.lastname: Gutiérrez-Cirlos
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Ordóñez-Sánchez
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Tusié-Luna
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Patterson
authors.forename: Gustav
authors.initials: G
authors.lastname: Schonfeld
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Aguilar-Salinas
mesh_terms: D000328:Adult; D053299:Apolipoprotein B-100 / Q000235:genetics*; D002247:Carbon Isotopes; D003625:Data Collection; D005234:Fatty Liver / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006761:Hospitals / Q000706:statistics & numerical data; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D007297:Inpatients / Q000706:statistics & numerical data; D007930:Leucine / Q000493:pharmacokinetics; D008099:Liver / Q000000981:diagnostic imaging; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D065626:Non-alcoholic Fatty Liver Disease; D010375:Pedigree; D011110:Polymorphism, Genetic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000235:genetics*; D014463:Ultrasonography
chemical_list: D053299:Apolipoprotein B-100; D002247:Carbon Isotopes; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D007930:Leucine