Germline mutations in the ribonuclease L gene in families showing linkage with HPC1
Germline mutations in the ribonuclease L gene in families showing linkage with HPC1
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DOI：
10.1038/ng823
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发表时间：
2002-02-01
期刊：
影响因子：
30.8
通讯作者：
Trent, J
中科院分区：
文献类型：
--
作者：
Carpten, J;Nupponen, N;Trent, J
虽然前列腺癌是美国男性中最常见的非皮肤恶性肿瘤（1，2），但对影响其遗传易感性的遗传因素知之甚少（3-5）。在此，我们报告了在前列腺癌家族中编码2 - 5 '-寡腺苷酸（2-5A）依赖性RNase L（RNASEL）（6-8）的基因中的种系突变分离，这些突变显示与1 q24 - 2 - 5处的HPC 1（遗传性前列腺癌1）区域存在连锁（参考文献9）。我们通过定位克隆/候选基因方法鉴定了RNASEL，并表明在两个HPC 1连锁家族中RNASEL的起始密码子中的无义突变和突变独立分离。无活性的RNASEL等位基因在一般人群中以低频率存在。RNASEL通过干扰素调节的2-5A途径调节细胞增殖和凋亡，并被认为是候选肿瘤抑制基因（10-12）。我们发现，显微解剖肿瘤与生殖系突变表现出杂合性和RNA酶L蛋白的损失，并RNASEL活性降低淋巴母细胞从杂合子个体相比，家庭成员谁是纯合子相对于野生型等位基因。因此，RNASEL中的生殖系突变可能具有诊断价值，2-5A通路可能为前列腺癌患者提供开发治疗方法的机会。
Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States(1,2), little is known about inherited factors that influence its genetic predisposition(3-5). Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL)(6-8) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene(10-12). We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.