New mutations in APOB100 involved in familial hypobetalipoproteinemia Klaus Brusgaard, MSc, PhD * , Lars Kjaersgaard, MD, PhD, Anne-Birthe Bo Hansen, MD, PhD, Steffen Husby, MD, PhD Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, DK–5000 Odense C, Denmark (Drs. Brusgaard and Hansen); and Hans Christian Andersen Children’s Hospital (Drs. Kjaersgaard and Husby) KEYWORDS: APOB100; LDL; Hypolipoproteinemia; Mutation; Malabsorption; Vitamin deficiency Abstract: Familial hypolipoproteinemia (FHBL) is characterized by an inherited low plasma level of apolipoprotein B containing lipoproteins. FHBL may be caused by mutations of APOB. Individuals with FHBL typically have intestinal malabsorption and frequently suffer from a deficiency of fat- soluble vitamins. Most mutations that cause FHBL are APOB truncating mutations. Here we describe a patient with FHBL caused by a novel truncating mutation together with a novel missense mutation. Ó 2010 National Lipid Association. All rights reserved. Familial hypobetalipoproteinemia (FHBL) is the result of an inherited low plasma level of apolipoprotein B- containing lipoproteins. 1 Apolipoprotein B (APOB100) is a large amphipathic glycoprotein that is synthesized in the liver and is a major apolipoprotein of very-low-density lip- oprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL). 2 FHBL may be caused by mutations of the apolipoprotein B (APOB) gene. Reduced levels of LDL accompany a single gene mutation without significant clinical consequences because one functional gene is sufficient for lipid transport. 2 When a mutation- producing dysfunction exists on both chromosomal copies of the APOB gene, a homozygous, or compound heterozy- gous defect, profound reduction of LDL, VLDL, and chy- lomicrons are evident. Such patients have intestinal malabsorption and frequently experience a deficiency of fat-soluble vitamins. Most mutations that cause FHBL are APOB-truncating mutations. Here we describe a patient with FHBL caused by a novel-truncating mutation in one chromosome and a novel missense mutation in the other. The majority of such cases of FHBL are caused by either frame-shift or missense mutations of the APOB gene. Pa- tients that are homozygous or compound heterozygous for FHBL mutations have extremely low levels of APOB. At the same time, the clinical phenotype of FHBL homozygotes is highly variable and only the severe cases present clinically evident fat and fat soluble vitamin malabsorption. They may also have acanthocytosis, retinitis pigmentosa, as well as neurological complications resulting from intestinal malab- sorption of vitamin E. 3,4 Other causes of low betalipoprotein are mutations in the microsomal triglyceride transfer protein, which lead to the autosomal-recessive disorder abetalipoproteinemia or to chylomicron retention disease (CRD). CRD embraces several clinical subsyndromes such as Anderson disease and Marinesco-Sjogren syndrome, caused by mutations in the SAR1B or the SIL1 gene, respectively. 5,6 Clinical symp- toms observed in patients with homozygous APOB100 FHBL can be indistinguishable from those arising from mutations in microsomal triglyceride transfer protein. However, individuals with FHBL are generally said to be * Corresponding author. E-mail address: Klaus.brusgaard@ouh.fyns-amt.dk Submitted December 14, 2009. Accepted for publication February 16, 2010. 1933-2874/$ -see front matter Ó 2010 National Lipid Association. All rights reserved. doi:10.1016/j.jacl.2010.02.009 Journal of Clinical Lipidology (2010) 4, 181–184