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Abstract-We studied a Syrian family with 3 children who had low-density lipoprotein cholesterol (LDL) concentrations of 13.3, 12.2, and 8.6 mmol/L, respectively. Three other siblings and the parents all had LDL values Ͻ4.52 mmol/L, suggesting an autosomal-recessive mode of inheritance. The extended pedigree had 66 additional persons with normal LDL values. A genome-wide scan in the core family with 427 markers showed support for linkage on both chromosomes 1 and 13. Markers on chromosome 1 revealed a 3.07 multipoint LOD score between 1p36.1-p35, an 18-cM interval. Surprisingly, we also found linkage to 13q22-q32, a 14-cM interval, with a 3.08 LOD score. We had identified this locus earlier as containing a gene strongly influencing LDL in another Arab family with autosomal-dominant familial hypercholesterolemia and in normal dizygotic twins. We found evidence for an interaction between these loci. We next genotyped our twin panel and confirmed linkage of the 1p36.1-p35 locus to LDL (PϽ0.002) in this normal population. Elucidation of ARH, the LDL receptor adaptor protein at chromosome 1p35, caused us to sequence that gene. We first identified the genomic structure of ARH gene and then sequenced the gene in our family. We found an intron 1 acceptor splice-site mutation. This mutation was not found in any other family members, in 31 nonrelated Syrian persons, or in 30 Germans. Our results underscore the importance of ARH on chromosome 1 and the chromosome 13q locus to LDL, not only in families with unusual illnesses, but also to the general population. Key Words: cholesterol Ⅲ LDL Ⅲ hyperlipidemia Ⅲ genetics Ⅲ familial hypercholesterolemia E levated plasma low-density lipoprotein cholesterol (LDL) concentrations, an important risk factor for atherosclerosis, are influenced by genetic factors. Elucidation of monogenic lipid disturbances has contributed greatly to our understanding of these disorders specifically and to lipid metabolism in general. [1][2][3][4] Ciccarese et al 5 described families from Sardinia in whom hypercholesterolemia is inherited in an autosomal-recessive fashion (ARH). They studied 5 families and were successful in mapping an ARH locus to chromosome 15q25-q26, which they termed ARH-1. Eden et al 6 and this study independently show that the autosomalrecessive familial hypercholesterolemia gene maps to chromosome 1p36.1-p35 (ARH). Recently, Garcia et al 7 succeeded in cloning the gene residing at the chromosome 1p35 locus. The gene codes for a putative LDL receptor adaptor protein.In an earlier study, we found linkage of unexpectedly low LDL values in a family with autosomal-dominant familial hypercholesterolemia (FH) to a locus on chromosome 13q. 8 We now report novel findings in an Arab kindred with ARH. We describe linkage to both the chromosome 1p35 and chromosome 13q loci, as well as evidence for an interaction between these loci. We identified the responsible mutation in the gene on 1p35 encoding for the LDL receptor adaptor protein and described the intron-exon structure of the gene. Fina...