Abstract
Familial hypobetalipoproteinemia (FHBL) is a genetically heterogeneous condition characterized by very low apolipoprotein B (apoB) concentrations in plasma and/or low levels of LDL-cholesterol (LDL-C) with a propensity to developing fatty liver. In a minority of cases, truncation-specifying mutations of the apoB gene (APOB) are etiologic, but the genetic basis of most cases is unknown. We previously reported linkage of FHBL to a 10 cM region on 3p21.1-22 in one kindred. The objectives of the current study were to identify other FHBL families with linkage to 3p and to narrow the FHBL susceptibility region on 3p. Six additional FHBL kindreds unlinked to the APOB region on chromosome 2 were genotyped with polymorphic markers spanning a region of approximately 13 cM on chromosome 3. Quantitative linkage analyses indicated that the FHBL in these families was linked to 3p21.1-22. Haplotype analysis identified several meiotic crossover events, allowing us to narrow the critical region from 10 cM to 2.0 cM, between markers D3S2407 and D3S1767. —Neuman, R. J., B. Yuan, D. S. Gerhard, K-Y. Liu, P. Yue, S. Duan, M. Averna, and G. Schonfeld. Replication of linkage of familial hypobetalipoproteinemia to chromosome 3p in six kindreds.
Highlights
Familial hypobetalipoproteinemia (FHBL) is a genetically heterogeneous condition characterized by very low apolipoprotein B concentrations in plasma and/ or low levels of LDL-cholesterol (LDL-C) with a propensity to developing fatty liver
Familial hypobetalipoproteinemia (FHBL) is a disorder of lipoprotein metabolism characterized by extremely low levels of LDL-cholesterol (LDL-C) and/or apolipoprotein B, segregating as an autosomal dominant trait [1,2,3]
ApoB-100 is secreted by the liver in VLDL particles and apolipoprotein B (apoB)-48 is secreted by the small intestine in chylomicrons [2]
Summary
Familial hypobetalipoproteinemia (FHBL) is a genetically heterogeneous condition characterized by very low apolipoprotein B (apoB) concentrations in plasma and/ or low levels of LDL-cholesterol (LDL-C) with a propensity to developing fatty liver. Truncation-producing mutations of APOB are found only in a small minority of kindreds with FHBL (6 –8), and the genetic etiologies are not well understood in the overwhelming majority of cases [7]. Quantitative trait loci (QTL) analysis indicated that 7 of the 21 pedigrees were not linked to the apoB region. These families were genotyped with markers mapped to 3p21.1-22. To further narrow the susceptibility locus, we performed haplotype analysis in one of the pedigrees with crossovers in the critical region These analyses implicated a 2 cM region on 3p that may harbor a genetic susceptibility locus for FHBL
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