Arca Marcello, Zuliani Giovanni, Wilund Kenneth, Campagna Filomena, Fellin Renato, Bertolini Stefano, Calandra Sebastiano, Ricci Giorgio, Glorioso Nicola, Maioli Mario, Pintus Paolo, Carru Ciriaco, Cossu Fausto, Cohen Jonathan, Hobbs Helen H
Department of Medical Therapy, University of Rome La Sapienza, Italy.
Lancet. 2002 Mar 9;359(9309):841-7. doi: 10.1016/S0140-6736(02)07955-2.
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.
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.
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.
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.
常染色体隐性高胆固醇血症（ARH）由一种名为ARH的假定衔接蛋白的突变引起。这种隐性疾病的特征是严重高胆固醇血症、黄瘤病和早发性冠状动脉疾病，除了在意大利撒丁岛外较为罕见。我们的目的是确定为何ARH在撒丁岛比在其他地方更常见。
我们获取了详细的病史，进行了体格检查，测量了脂蛋白浓度，并从17个无关家族的28名患有ARH的撒丁岛人身上采集了基因组DNA。我们对这些家族的先证者以及40名非撒丁岛血统、患有病因不明的常染色体隐性高胆固醇血症的个体的ARH编码区和共有剪接位点进行了测序。
在所有17个患有ARH的无关家族中均存在两种ARH突变，即外显子4中的移码突变（c432insA，ARH1）和外显子1中的无义突变（c65G→A，ARH2）。由于ARH1和ARH2之间的古老重组，三个ARH等位基因同时包含这两种突变。在撒丁岛内，这三个突变等位基因没有明显的区域聚集现象。此外，来自意大利大陆的四名患有常染色体隐性高胆固醇血症的个体为ARH1纯合子。
撒丁岛上ARH突变的数量少、频率高且分布分散，这与这些突变古老且由于地理隔离而在撒丁岛人群中得以保留的情况相符。
