TY - JOUR
T1 - Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH
T2 - A clinical and molecular genetic analysis
AU - Arca, Marcello
AU - Zuliani, Giovanni
AU - Wilund, Kenneth
AU - Campagna, Filomena
AU - Fellin, Renato
AU - Bertolini, Stefano
AU - Calandra, Sebastiano
AU - Ricci, Giorgio
AU - Glorioso, Nicola
AU - Maioli, Mario
AU - Pintus, Paolo
AU - Carru, Ciriaco
AU - Cossu, Fausto
AU - Cohen, Jonathan
AU - Hobbs, Helen H.
N1 - Funding Information:
We thank Tommy Hyatt and Robert Barnes for their assistance with the molecular characterisation of ARH alleles; Anna Montali for technical assistance; and Michael S Brown and Joseph L Goldstein for provision of some of the cell lines used. This work was sponsored by Telethon Grant E-0565 and E-0947 (MA and SB, respectively), NIH HL20948, HL47619, Donald W Reynolds Cardiovascular Clinical Research Center, and the W M Keck Foundation (HHH) and NIH training grant HL07360 (KW).
PY - 2002/3/9
Y1 - 2002/3/9
N2 - 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. Findings. 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. Interpretation. 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.
AB - 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. Findings. 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. Interpretation. 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.
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U2 - 10.1016/S0140-6736(02)07955-2
DO - 10.1016/S0140-6736(02)07955-2
M3 - Article
C2 - 11897284
AN - SCOPUS:0037045847
SN - 0140-6736
VL - 359
SP - 841
EP - 847
JO - Lancet
JF - Lancet
IS - 9309
ER -