Primary
hypobetalipoproteinemia (HBL) includes a group of
genetic disorders:
abetalipoproteinemia (ABL) and
chylomicron retention disease (CRD), with a recessive transmission, and
familial hypobetalipoproteinemia (FHBL) with a co-dominant transmission. ABL and CRD are rare disorders due to mutations in the MTP and SARA2 genes, respectively. Heterozygous FHBL is much more frequent. FHBL subjects often have
fatty liver and, less frequently, intestinal fat malabsorption. FHBL may be linked or not to the
APOB gene. Most mutations in
APOB gene cause the formation of truncated forms of
apoB which may or may be not secreted into the plasma. Truncated apoBs with a size below that of apoB-30 are not detectable in plasma; they are more frequent in patients with the most severe phenotype. Only a single amino acid substitution (R463W) has been reported as the cause of FHBL. Approximately 50% of FHBL subjects are carriers of pathogenic mutations in
APOB gene; therefore, a large proportion of FHBL subjects have no
apoB gene mutations or are carriers of rare amino acid substitutions in
apoB with unknown effect. In some kindred FHBL is linked to a locus on chromosome 3 (3p21) but the candidate gene is unknown. Recently a FHBL plasma
lipid phenotype was observed in carriers of mutations of the PCSK9 gene causing loss of function of the encoded
protein, a proprotein convertase which regulates
LDL-receptor number in the liver. Inactivation of this
enzyme is associated with an increased
LDL uptake and
hypobetalipoproteinemia. HBL carriers of PCSK9 mutations do not develop
fatty liver disease.