Clinical features and genetic analysis of autosomal recessive hypercholesterolemia
Clinical features and genetic analysis of autosomal recessive hypercholesterolemia
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DOI：
10.1210/jc.2002-021487
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发表时间：
2003-06-01
影响因子：
5.8
通讯作者：
Yamamoto, A
中科院分区：
文献类型：
--
作者：
Harada-Shiba, M;Takagi, A;Yamamoto, A
以前，我们曾报道过严重的高胆固醇血症，黄色瘤，和过早的动脉粥样硬化的兄弟姐妹没有任何损害的低密度脂蛋白受体在他们的成纤维细胞作为常染色体隐性高胆固醇血症（ARH）的第一个特征。最近，突变被确定为这种疾病的基因编码一个假定的衔接蛋白。本研究的目的是探讨日本同胞ARH的分子发病机制。在兄弟姐妹的ARH基因中发现了一种新的插入突变。在外显子6的位置599至606处包含8个连续胞嘧啶的基因座中鉴定了额外胞嘧啶残基的插入，产生9个胞嘧啶的序列并在657 - 659处产生早期终止密码子。母亲是这种突变的杂合子。在纯合子患者的成纤维细胞中未检测到ARH的转录产物和蛋白。在正常对照受试者中发现了604位的单核苷酸多态性（胞嘧啶至胸腺嘧啶：ARH-604 C至ARH-604 T），该多态性将202位的脯氨酸残基改变为丝氨酸。有趣的是，ARH是由同一位置的胞嘧啶突变为腺嘌呤引起的。两个兄弟姐妹都表现出脂肪肝，这也可能与这种突变有关。
Previously we have reported on siblings with severe hypercholesterolemia, xanthomas, and premature atherosclerosis without any impairment of low-density lipoprotein receptor in their fibroblasts as a first characterization of autosomal recessive hypercholesterolemia (ARH). Recently, mutations were identified for this disease in a gene encoding a putative adaptor protein. The purpose of this study was to examine the molecular pathogenesis of ARH in Japanese siblings. A novel insertion mutation was discovered in the ARH gene of the siblings. An insertion of an extra cytosine residue was identified in a locus comprising eight consecutive cytosines at positions 599 through 606 in exon 6, resulting in a sequence of nine cytosines and generating an early stop codon at 657 - 659. The mother was heterozygous for this mutation. Neither transcription product nor protein of ARH was detected in the fibroblasts of the homozygous patients. A single nucleotide polymorphism was discovered among the normal control subjects at position 604 ( cytosine to thymine: ARH-604C to ARH-604T), which changes the proline residue at 202 to serine. Interestingly, ARH is caused by a mutation of cytosine to adenine at this same position. Both siblings exhibited fatty liver, which may also be related to this mutation.