title: Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis.
abstract: BACKGROUND
  Autosomal recessive hypercholesterolaemia (ARH) is caused by mutations in a putative adaptor protein called ARH. This recessive disorder, characterised by severe hypercholesterolaemia, xanthomatosis, and premature coronary artery disease, is rare except on the island of Sardinia, Italy. Our aim was to ascertain why ARH is more common on Sardinia than elsewhere.
  
  
  METHODS
  We obtained detailed medical histories, did physical examinations, measured concentrations of lipoproteins, and harvested genomic DNA from 28 Sardinians with ARH from 17 unrelated families. We sequenced the coding regions and consensus splice sites of ARH in probands from these families, and from 40 individuals of non-Sardinian origin who had an autosomal recessive form of hypercholesterolaemia of unknown cause.
  
  
  RESULTS
  Two ARH mutations, a frameshift mutation (c432insA) in exon 4 (ARH1) and a nonsense mutation (c65G-->A) in exon 1 (ARH2), were present in all of the 17 unrelated families with ARH. Three of the ARH alleles contained both mutations, as a result of an ancient recombination between ARH1 and ARH2. No regional clustering of the three mutant alleles within Sardinia was apparent. Furthermore, four Italians from the mainland with autosomal recessive hypercholesterolaemia were homozygous for ARH1.
  
  
  CONCLUSIONS
  The small number, high frequency, and dispersed distribution of ARH mutations on Sardinia are consistent with these mutations being ancient and maintained in the Sardinian population because of geographic isolation.
authors.affiliation: Department of Medical Therapy, University of Rome La Sapienza, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Arca
authors.forename: Giovanni
authors.initials: G
authors.lastname: Zuliani
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wilund
authors.forename: Filomena
authors.initials: F
authors.lastname: Campagna
authors.forename: Renato
authors.initials: R
authors.lastname: Fellin
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ricci
authors.forename: Nicola
authors.initials: N
authors.lastname: Glorioso
authors.forename: Mario
authors.initials: M
authors.lastname: Maioli
authors.forename: Paolo
authors.initials: P
authors.lastname: Pintus
authors.forename: Ciriaco
authors.initials: C
authors.lastname: Carru
authors.forename: Fausto
authors.initials: F
authors.lastname: Cossu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cohen
authors.forename: Helen H
authors.initials: HH
authors.lastname: Hobbs
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006239:Haplotypes; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D008967:Molecular Biology; D009154:Mutation
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors