title: Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.
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 <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.
authors.affiliation: Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
authors.forename: Hussam
authors.initials: H
authors.lastname: Al-Kateb
authors.forename: Sylvia
authors.initials: S
authors.lastname: Bähring
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.forename: Andreas
authors.initials: A
authors.lastname: Busjahn
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Muhidien
authors.initials: M
authors.lastname: Jouma
authors.forename: Eckehard K F
authors.initials: EK
authors.lastname: Bautz
authors.forename: Hans A
authors.initials: HA
authors.lastname: Dresel
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
mesh_terms: D001483:Base Sequence; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D005192:Family Health; D005260:Female; D005796:Genes / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics*; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D013593:Syria; D014280:Triglycerides / Q000097:blood
chemical_list: D008076:Cholesterol, HDL; D014280:Triglycerides; D002784:Cholesterol