期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：22
页码：10148-10153
DOI：10.1073/pnas.0913125107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：We have studied models of telomerase haploinsufficiency in humans and mice to analyze regulation of telomere length and the significance of "set points" in inheritance of telomere length. In three families with clinical syndromes associated with short telomeres resulting from haploinsufficient mutations in TERT, the gene encoding telomerase reverse transcriptase, we asked whether restoration of normal genotypes in offspring of affected individuals would elongate inherited short telomeres. Telomeres were shorter than normal in some but not all genotypically normal offspring of telomerase-mutant parents or grandparents. Analysis of these findings was complicated by heterogeneity of telomere length among individuals, as well as by the admixing of telomeres inherited from affected parents with those inherited from unaffected ("wild-type" TERT) parents. To understand further the inheritance of telomere length, we established a shortened-telomere mouse model. When Tert+/- heterozygous mice were successively cross-bred through 17 generations, telomere length shortened progressively. The late-generation Tert+/- mice were intercrossed to produce genotypically wild-type Tert+/+ mice, for which telomere length was characterized. Strikingly, telomere length in these Tert+/+ mice was not longer than that of their Tert+/- parents. Moreover, when successive crosses were carried out among these short-telomere Tert+/+ offspring mice, telomere length was stable, with no elongation up to six generations. This breeding strategy therefore has established a mouse strain, B6.ST (short telomeres), with C57BL/6 genotype and stable short telomeres. These findings suggest that the set point of telomere lengths of offspring is determined by the telomere lengths of their parents in the presence of normal expression of telomerase.
