Familial defective apolipoprotein B-100: Haplotype analysis of the arginine₍₃₅₀₀₎ → glutamine mutation

Familial defective apolipoprotein B-100 (FDB) is a recently identified, dominantly inherited genetic disorder, which leads to an increased serum level of low density lipoprotein (LDL) cholesterol with reduced affinity for the LDL receptor. It is postulated that this disorder results from a G to A mutation at nucleotide 10 708 in exon 26 of the apo B gene creating a substitution of glutamine for arginine in the codon for amino acid 3500. To investigate whether recurrent mutation has contributed to the high frequency of FDB, we have conducted a haplotype analysis in previously reported and newly detected FDB heterozygotes in Germany. 5 FDB families and 6 unrelated FDB heterozygotes were genotypes at 4 polymorphic sites in the 3′ end of the apo B gene. These sites consisted of the diallelic markers XbaI, MspI, EcoRI and the hypervariable region (3′HVR). In 5 FDB families and 1 unrelated FDB heterozygote the arginine₍₃₅₀₀₎ → glutamine mutation could be unambiguously assigned to the haplotype XbaI^-/MspI⁺/EcoRI^-/3′HVR48, in the other 5 FDB unrelated heterozygotes this finding was consistent with the combination of the genotype. The existence of the arginine₍₃₅₀₀₎ → glutamine mutation on the same and supposedly rare allele suggests that the mutant alleles are identical by descent in our population. The fact that the same mutant allele was identified in North America and Austria suggests a common European origin of the arginine₍₃₅₀₀₎ → glutamine mutation.