GENETIC-HETEROGENEITY IN FAMILIAL HYPOBETALIPOPROTEINEMIA - LINKAGE AND NON-LINKAGE TO THE APO-B GENE IN CAUCASIAN FAMILIES

Familial hypobetalipoproteinemia (FHBL) is an autosomal dominant disor der of lipid metabolism characterized by extremely low plasma levels o f apolipoprotein B (apoB), and total-, and low-density lipoprotein (LD L) cholesterol. Various truncated forms of apoB have been found to cos egregate with the FHBL phenotype in more than 30 kindreds. By contrast , no truncated forms of apoB protein were detected with sensitive immu noblotting in the plasmas of any of the 6 kindreds reported here. Indi viduals with apoB levels in the 5th centile for their age and sex were considered as affected with FHBL. Linkage analysis was performed usin g 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 theta = 0 fo r 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 f amily (F kindred) from the other five, LOD scores of -25.2 at the 3' V NTR and -7.8 at the intragenic apoB/Xbal marker at theta = 6 excluded linkage to the apoB gene in the F kindred. These kindreds demonstrate the heterogeneity of FHBL and also offer the possibility to investigat e as yet undescribed mutations of apoB, resulting in alterations of ap oB metabolism. The F kindred may shed light on novel gene(s) contribut ing to the low apoB-phenotype. (C) 1998 Wiley-Liss, Inc.