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(Circulation Research. 2002;90:951.)
© 2002 American Heart Association, Inc.

Clinical Research

Mutation in the ARH Gene and a Chromosome 13q Locus Influence Cholesterol Levels in a New Form of Digenic-Recessive Familial Hypercholesterolemia

Hussam Al-Kateb, Sylvia Bähring, Katrin Hoffmann, Konstantin Strauch, Andreas Busjahn, Gudrun Nürnberg, Muhidien Jouma, Eckehard K.F. Bautz, Hans A. Dresel, Friedrich C. Luft

From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine (H.A.-K., S.B., K.H., A.B., G.N., F.C.L.), Medical Faculty of the Charité, Humboldt University of Berlin, Germany; the Department of Biochemistry (H.A.-K., M.J.), College of Pharmacy, University of Damascus, Syria; Institute of Molecular Genetics and Faculty of Medicine (H.A.-K., E.K.F.B., H.A.D.), University of Heidelberg; Institute for Medical Biometry (K.S.), Informatics and Epidemiology, University of Bonn; and Infogen GmbH (A.B.), subsidiary of Valigen NV, Berlin, Germany.

Correspondence to Friedrich C. Luft, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de

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 <4.52 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 (P<0.002) 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 • LDL • hyperlipidemia • genetics • familial hypercholesterolemia

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