Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene
Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene
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DOI：
10.1182/blood-2007-10-120907
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发表时间：
2008-02-01
期刊：
影响因子：
20.3
通讯作者：
Bessler, Monica
中科院分区：
文献类型：
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作者：
Du, Hong-Yan;Pumbo, Elena;Bessler, Monica
端粒酶组分逆转录酶TERT和RNA模板TERC中的杂合突变，由于端粒缩短而引起常染色体显性遗传先天性角化不良。预期，即疾病的严重程度增加，在后代由于遗传较短的端粒，是这种情况的一个特点。在这里，我们描述了2个家庭，其中2个TERT突变分离。两个家系都含有复合杂合子。在一种情况下，先证者是纯合子的新突变引起P704S取代，而他父亲的第二个等位基因编码H412Y突变。第二个家系的先证者具有突变等位基因Y846C和H876Q。转染研究显示突变等位基因的共显性表达，没有显性负效应或基因内互补的证据。因此，在这些家庭中，两个TERT等位基因的表达和遗传端粒长度有助于临床表型。
Heterozygous mutations in the telomerase components TERT the reverse transcriptase, and TERC, the RNA template, cause autosomal dominant dyskeratosis congenita due to telomere shortening. Anticipation, whereby the disease severity increases in succeeding generations due to inheritance of shorter telomeres, is a feature of this condition. Here we describe 2 families in which 2 TERT mutations are segregating. Both families contain compound heterozygotes. In one case the proband is homozygous for a novel mutation causing a P704S substitution, while his father's second allele encodes an H412Y mutation. The proband in the second family has mutant alleles Y846C and H876Q. Transfection studies show codominant expression of the mutated alleles with no evidence of a dominant negative effect or of intragenic complementation. Thus in these families the expression of both TERT alleles and the inherited telomere length contribute to the clinical phenotype.