Finette B A, Rood B, Poseno T, Vacek P, Pueschel S, Homans A C
Department of Pediatrics, University of Vermont, Burlington 05401, USA.
Mutat Res. 1998 Jul 17;403(1-2):35-43. doi: 10.1016/s0027-5107(98)00024-4.
People with Down syndrome are 10-30 fold more likely to develop leukemia than the normal population. To date, little is known regarding the molecular mechanisms underlying this phenomenon. We have previously demonstrated that the spontaneous somatic mutant frequency (Mf) at a reporter gene, hypoxanthine-guanine phosphoribosyl transferase (HPRT), from a normal population showed a strict age dependency with an exponential increase in Mf from birth to late adolescents with a subsequent linear 2-5% increase per year in adults. In this study, we compared HPRT Mf in children and adults with Down syndrome using the HPRT T-cell cloning assay. We determined the Mf at the HPRT locus in 27 subjects with Down syndrome from ages 6 months to 53.4 years. Results demonstrated that background somatic Mf at the HPRT locus in children and adults with Down syndrome are not dependent on age as seen in a normal control population. Results also show that adults with Down syndrome have a significantly lower Mf than normal adults, and that children with Down syndrome have a significantly higher Mf than normal children, although the latter appears to be due to a decreased cloning efficiency (CE). These observations demonstrate that the frequency of spontaneous somatic mutations in children and adults with Down syndrome are atypical compared to normal controls, and suggest that the genetic mechanisms associated with background somatic mutational events in children and adults with Down syndrome may be different.
唐氏综合征患者患白血病的可能性是正常人群的10至30倍。迄今为止，对于这一现象背后的分子机制知之甚少。我们之前已经证明，来自正常人群的报告基因次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶（HPRT）的自发体细胞突变频率（Mf）显示出严格的年龄依赖性，从出生到青少年后期Mf呈指数增长，随后在成年人中每年线性增长2 - 5％。在本研究中，我们使用HPRT T细胞克隆测定法比较了唐氏综合征儿童和成人的HPRT Mf。我们测定了27名年龄在6个月至53.4岁之间的唐氏综合征患者HPRT基因座处的Mf。结果表明，唐氏综合征儿童和成人HPRT基因座处的背景体细胞Mf不像正常对照人群那样依赖于年龄。结果还表明，唐氏综合征成人的Mf明显低于正常成人，唐氏综合征儿童的Mf明显高于正常儿童，尽管后者似乎是由于克隆效率（CE）降低所致。这些观察结果表明，与正常对照相比，唐氏综合征儿童和成人的自发体细胞突变频率是非典型的，并表明与唐氏综合征儿童和成人背景体细胞突变事件相关的遗传机制可能不同。
