Hakoda M, Kamatani N, Kurumada S, Hirai Y, Sakamoto K, Yamanaka H, Terai C, Kashiwazaki S
Institute of Rheumatology, Tokyo Women's Medical College KS BLDG, Japan.
Hum Genet. 1997 Feb;99(2):164-70. doi: 10.1007/s004390050332.
Both germline and somatic mutations are known to affect phenotypes of human cells in vivo. In previous studies, we cloned mutant peripheral blood T cells from germline heterozygous humans for adenine phosphoribosyltransferase (APRT) (EC 2.4.2.7) deficiency and found that approximately 1.3 x 10-4 peripheral T cells had undergone in vivo somatic mutations. Loss of heterozygosity (LOH) was the major cause of the mutations at the APRT locus since approximately 80% of the mutant T cell clones exhibited loss of normal alleles. In the present study, we identified three heterozygous individuals for APRT deficiency (representing two separate families), in whom none of the somatic mutant cells exhibited LOH at the APRT locus. The germline mutant APRT alleles of these heterozygotes from two unrelated families had the same gross DNA abnormalities detectable by Southern blotting. None of the germline mutant APRT alleles so far reported had such gross DNA abnormalities. The data suggest that the germline mutation unique to these heterozygous individuals is associated with the abrogation of LOH in somatic cells. The absence of LOH at a different locus has already been reported in vitro in an established cell line but the present study describes the first such event in vivo in human individuals.
已知种系突变和体细胞突变都会影响体内人类细胞的表型。在先前的研究中，我们从患有腺嘌呤磷酸核糖转移酶（APRT）（EC 2.4.2.7）缺乏症的种系杂合人类中克隆了突变的外周血T细胞，发现约1.3×10-4的外周T细胞发生了体内体细胞突变。杂合性缺失（LOH）是APRT基因座突变的主要原因，因为约80%的突变T细胞克隆表现出正常等位基因的缺失。在本研究中，我们鉴定出三名APRT缺乏症的杂合个体（代表两个不同的家族），其中没有一个体细胞突变细胞在APRT基因座表现出LOH。来自两个无关家族的这些杂合子的种系突变APRT等位基因具有通过Southern印迹可检测到的相同的总体DNA异常。迄今为止报道的种系突变APRT等位基因均没有这种总体DNA异常。数据表明，这些杂合个体特有的种系突变与体细胞中LOH的消除有关。在一个已建立的细胞系中，体外已报道在不同基因座不存在LOH，但本研究描述了人类个体体内首次出现这种情况。
