Telomerase reverse transcriptase haploinsufficiency and telomere length in individuals with 5p-syndrome
Telomerase reverse transcriptase haploinsufficiency and telomere length in individuals with 5p-syndrome
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DOI：
10.1111/j.1474-9726.2007.00324.x
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发表时间：
2007-10-01
期刊：
影响因子：
7.8
通讯作者：
Bessler, Monica
中科院分区：
文献类型：
--
作者：
Du, Hong-Yan;Idol, Rachel;Bessler, Monica
维持染色体末端的端粒酶由两个核心组分组成，即端粒酶逆转录酶（TERT）和端粒酶RNA（TERC）。TERC或TERT的单倍不足导致进行性端粒缩短和常染色体显性遗传先天性角化不良（DC）。常染色体显性遗传DC的临床表现被认为发生在端粒变得非常短的时候，但是在这种情况下端粒缩短的速率是未知的。在这里，我们研究了在一个大的5 p-综合征个体队列中从头TERT基因缺失的后果。研究组包括41名个体，其中染色体缺失导致5p15.33处的一个拷贝的TERT基因丢失。这些个体外周血细胞中的端粒长度虽然在正常范围内，但平均比正常对照组短。缩短在老年人中更为显着，表明加速的年龄依赖性缩短。相比之下，由于遗传性TERC基因缺失而患有常染色体显性DC的个体具有非常短的端粒，并且无论年龄如何，端粒都同样短。尽管一些患有5 p-综合征的个体显示出令人想起常染色体显性DC的临床特征，但这些特征与端粒长度无关，表明这些不是由非常短的端粒引起的。我们的结论是，一个端粒酶逆转录酶基因的缺失导致在一代端粒稍短。然而，我们的研究结果表明，需要几代的TERT单倍不足，以产生非常短的端粒在患者与DC。
Telomerase, which maintains the ends of chromosomes, consists of two core components, the telomerase reverse transcriptase (TERT) and the telomerase RNA (TERC). Haploinsufficiency for TERC or TERT leads to progressive telomere shortening and autosomal dominant dyskeratosis congenita (DC). The clinical manifestations of autosomal dominant DC are thought to occur when telomeres become critically short, but the rate of telomere shortening in this condition is unknown. Here, we investigated the consequences of de novo TERT gene deletions in a large cohort of individuals with 5p- syndrome. The study group included 41 individuals in which the chromosome deletion resulted in loss of one copy of the TERT gene at 5p15.33. Telomere length in peripheral blood cells from these individuals, although within the normal range, was on average shorter than in normal controls. The shortening was more significant in older individuals suggesting an accelerated age-dependent shortening. In contrast, individuals with autosomal dominant DC due to an inherited TERC gene deletion had very short telomeres, and the telomeres were equally short regardless of the age. Although some individuals with 5p- syndrome showed clinical features that were reminiscent of autosomal dominant DC, these features did not correlate with telomere length, suggesting that these were not caused by critically short telomeres. We conclude that a TERT gene deletion leads to slightly shorter telomeres within one generation. However, our results suggest that several generations of TERT haploinsufficiency are needed to produce the very short telomeres seen in patients with DC.