Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis.
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.
Arca
Marcello
M
Department of Medical Therapy, University of Rome La Sapienza, Italy.
Zuliani
Giovanni
G
Wilund
Kenneth
K
Campagna
Filomena
F
Fellin
Renato
R
Bertolini
Stefano
S
Calandra
Sebastiano
S
Ricci
Giorgio
G
Glorioso
Nicola
N
Maioli
Mario
M
Pintus
Paolo
P
Carru
Ciriaco
C
Cossu
Fausto
F
Cohen
Jonathan
J
Hobbs
Helen H
HH
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
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors