Genetic heterogeneity in familial hypobetalipoproteinemia: Linkage and non-linkage to the apoB gene in caucasian families

Familial hypobetalipoproteinemia (FHBL) is an autosomal dominant disorder of lipid metabolism characterized by extremely low plasma levels of apolipoprotein B (apoB), and total-, and low-density lipoprotein (LDL) cholesterol. Various truncated forms of apoB have been found to cosegregate with the FHBL phenotype in more than 30 kindreds. By contrast, no truncated forms of apoB protein were detected with sensitive immunoblotting in the plasmas of any of the 6 kindreds reported here. Individuals with apoB levels in the 5th centile for their age and sex were considered as affected with FHBL. Linkage analysis was performed using 3 microsatellite markers flanking the apoB gene (D2S131, D2S149, and D2S144), a 3′ variable number of tandem repeats (VNTR) marker and one intragenic marker. Two-point linkage of FHBL was established to the 3′ VNTR marker with a combined maximum LOD score of 8.5 at θ = 0 for 5 of the 6 families. Maximum LOD scores for flanking microsatellite markers were 5.0, 2.4, 1.3, 1.2 and 2.1 for these kindreds (D, T, De, C and Z, respectively). A test of homogeneity differentiated the 6th family (F kindred) from the other five. LOD scores of −25.2 at the 3′ VNTR and −7.8 at the intragenic apoB/Xbal marker at θ = 0 excluded linkage to the apoB gene in the F kindred. These kindreds demonstrate the heterogeneity of FHBL and also offer the possibility to investigate as yet undescribed mutations of apoB, resulting in alterations of apoB metabolism. The F kindred may shed light on novel gene(s) contributing to the low apoB-phenotype. Am. J. Med. Genet. 76:79–86, 1998. © 1998 Wiley-Liss, Inc.