Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Andrology. 2014 May;2(3):304-14. doi: 10.1111/j.2047-2927.2013.00175.x. Epub 2013 Dec 19.
Owing to a recent trend for delayed paternity, the genomic integrity of spermatozoa of older men has become a focus of increased interest. Older fathers are at higher risk for their children to be born with several monogenic conditions collectively termed paternal age effect (PAE) disorders, which include achondroplasia, Apert syndrome and Costello syndrome. These disorders are caused by specific mutations originating almost exclusively from the male germline, in genes encoding components of the tyrosine kinase receptor/RAS/MAPK signalling pathway. These particular mutations, occurring randomly during mitotic divisions of spermatogonial stem cells (SSCs), are predicted to confer a selective/growth advantage on the mutant SSC. This selective advantage leads to a clonal expansion of the mutant cells over time, which generates mutant spermatozoa at levels significantly above the background mutation rate. This phenomenon, termed selfish spermatogonial selection, is likely to occur in all men. In rare cases, probably because of additional mutational events, selfish spermatogonial selection may lead to spermatocytic seminoma. The studies that initially predicted the clonal nature of selfish spermatogonial selection were based on DNA analysis, rather than the visualization of mutant clones in intact testes. In a recent study that aimed to identify these clones directly, we stained serial sections of fixed testes for expression of melanoma antigen family A4 (MAGEA4), a marker of spermatogonia. A subset of seminiferous tubules with an appearance and distribution compatible with the predicted mutant clones were identified. In these tubules, termed 'immunopositive tubules', there is an increased density of spermatogonia positive for markers related to selfish selection (FGFR3) and SSC self-renewal (phosphorylated AKT). Here we detail the properties of the immunopositive tubules and how they relate to the predicted mutant clones, as well as discussing the utility of identifying the potential cellular source of PAE mutations.
由于最近出现了晚育趋势，因此人们越来越关注年长男性精子的基因组完整性。年长的父亲生育的孩子更容易患上几种单基因疾病，这些疾病统称为父龄效应（PAE）疾病，包括软骨发育不全、Apert 综合征和 Costello 综合征。这些疾病是由特定的突变引起的，这些突变几乎完全源自男性生殖细胞，存在于编码酪氨酸激酶受体/RAS/MAPK 信号通路组成部分的基因中。这些特定的突变在精原干细胞（SSC）的有丝分裂分裂过程中随机发生，预计会赋予突变的 SSC 选择性/生长优势。随着时间的推移，这种选择优势导致突变细胞的克隆扩张，从而使突变精子的产生水平显著高于背景突变率。这种现象称为自私性精原细胞选择，可能发生在所有男性中。在极少数情况下，可能由于额外的突变事件，自私性精原细胞选择可能导致精原细胞瘤。最初预测自私性精原细胞选择的克隆性质的研究是基于 DNA 分析，而不是在完整的睾丸中观察突变克隆。在最近的一项旨在直接识别这些克隆的研究中，我们对固定睾丸的连续切片进行了黑色素瘤抗原家族 A4（MAGEA4）的表达染色，MAGEA4 是精原细胞的标志物。鉴定出一组外观和分布与预测的突变克隆相匹配的生精小管。在这些称为“免疫阳性小管”的小管中，与自私选择（FGFR3）和 SSC 自我更新（磷酸化 AKT）相关的标记物阳性的精原细胞密度增加。在这里，我们详细描述了免疫阳性小管的特性以及它们与预测的突变克隆的关系，并讨论了识别 PAE 突变的潜在细胞来源的实用性。
