Sullivan Amy K, Crawford Dana C, Scott Elizabeth H, Leslie Mary L, Sherman Stephanie L
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Am J Hum Genet. 2002 Jun;70(6):1532-44. doi: 10.1086/340846. Epub 2002 May 3.
Fragile X syndrome, a form of X-linked mental retardation, results from the hyperexpansion of a CGG trinucleotide repeat located in the 5' untranslated region of the fragile X mental retardation (FMR1) gene. Relatively little is known about the initial mutation that causes a stable allele to become unstable and, eventually, to expand to the full mutation. In the present study, we have examined 1,452 parent-child transmissions of alleles of common (< or =39 repeats) or intermediate (40-59 repeats) sizes to study the initial mutation events. Of these, 201 have been sequenced and haplotyped. Using logistic regression analysis, we found that parental origin of transmission, repeat size (for unsequenced alleles), and number of the 3' CGGs (for sequenced alleles) were significant risk factors for repeat instability. Interestingly, transmission of the repeat through males was less stable than that through females, at the common- and intermediate-size level. This pattern differs from that seen for premutation-size alleles: paternally transmitted alleles are far more stable than maternally transmitted alleles. This difference that depends on repeat size suggests either a different mutational mechanism of instability or an increase in selection against sperm as their repeat size increases.
脆性X综合征是一种X连锁智力障碍疾病，由位于脆性X智力障碍1（FMR1）基因5'非翻译区的CGG三核苷酸重复序列过度扩增所致。对于导致稳定等位基因变得不稳定并最终扩展为完全突变的初始突变，人们了解得相对较少。在本研究中，我们检测了1452例常见（≤39次重复）或中等（40 - 59次重复）大小等位基因的亲子传递情况，以研究初始突变事件。其中，201例已进行测序和单倍型分析。通过逻辑回归分析，我们发现传递的亲本来源、重复大小（对于未测序的等位基因）以及3'端CGG的数量（对于已测序的等位基因）是重复序列不稳定的显著危险因素。有趣的是，在常见和中等大小水平上，重复序列通过男性传递比通过女性传递更不稳定。这种模式与前突变大小等位基因的情况不同：父系传递的等位基因比母系传递的等位基因稳定得多。这种取决于重复大小的差异表明，要么存在不同的不稳定突变机制，要么随着重复大小的增加，针对精子的选择作用增强。
