Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Skåne University Hospital, Malmö, Sweden.
PLoS One. 2013 Jul 22;8(7):e69097. doi: 10.1371/journal.pone.0069097. Print 2013.
The kallikrein gene family (KLK1-KLK15) is the largest contiguous group of protease genes within the human genome and is associated with both risk and outcome of cancer and other diseases. We searched for copy number variants in all KLK genes using quantitative PCR analysis and analysis of inheritance patterns of single nucleotide polymorphisms. Two deletions were identified: one 2235-bp deletion in KLK9 present in 1.2% of alleles, and one 3394-bp deletion in KLK15 present in 4.0% of alleles. Each deletion eliminated one complete exon and created out-of-frame coding that eliminated the catalytic triad of the resulting truncated gene product, which therefore likely is a non-functional protein. Deletion breakpoints identified by DNA sequencing located the KLK9 deletion breakpoint to a long interspersed element (LINE) repeated sequence, while the deletion in KLK15 is located in a single copy sequence. To search for an association between each deletion and risk of prostate cancer (PC), we analyzed a cohort of 667 biopsied men (266 PC cases and 401 men with no evidence of PC at biopsy) using short deletion-specific PCR assays. There was no association between evidence of PC in this cohort and the presence of either gene deletion. Haplotyping revealed a single origin of each deletion, with most recent common ancestor estimates of 3000-8000 and 6000-14 000 years for the deletions in KLK9 and KLK15, respectively. The presence of the deletions on the same haplotypes in 1000 Genomes data of both European and African populations indicate an early origin of both deletions. The old age in combination with homozygous presence of loss-of-function variants suggests that some kallikrein-related peptidases have non-essential functions.
激肽释放酶基因家族（KLK1-KLK15）是人类基因组中最大的连续蛋白酶基因群，与癌症和其他疾病的风险和结果都有关。我们使用定量 PCR 分析和单核苷酸多态性遗传模式分析，在所有 KLK 基因中搜索拷贝数变异。鉴定出两种缺失：一种是 KLK9 中的 2235 个碱基对缺失，存在于 1.2%的等位基因中，另一种是 KLK15 中的 3394 个碱基对缺失，存在于 4.0%的等位基因中。每个缺失消除了一个完整的外显子，并产生了无框架编码，消除了由此产生的截短基因产物的催化三联体，因此可能是一种无功能的蛋白质。通过 DNA 测序确定的缺失断点将 KLK9 缺失断点定位到长散在元件（LINE）重复序列，而 KLK15 的缺失位于单个拷贝序列中。为了研究每个缺失与前列腺癌（PC）风险之间的关联，我们使用短缺失特异性 PCR 检测分析了 667 例活检男性（266 例 PC 病例和 401 例活检无 PC 证据的男性）的队列。在该队列中，PC 的证据与两种基因缺失的存在均无关。单体型分析显示，每种缺失均来自单一起源，KLK9 和 KLK15 缺失的最近共同祖先估计分别为 3000-8000 和 6000-14000 年。1000 基因组数据中两种缺失在欧洲和非洲人群中的相同单体型上的存在表明，这两种缺失的起源都很早。这些缺失的古老年龄与功能丧失变异的纯合存在相结合，表明某些激肽释放酶相关肽酶具有非必需的功能。
