Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene.
Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene.
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DOI：
10.1002/humu.22397
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发表时间：
2013-11
期刊：
影响因子：
3.9
通讯作者：
Armanios, Mary
中科院分区：
文献类型：
--
作者：
Alder, Jonathan K.;Parry, Erin M.;Yegnasubramanian, Srinivasan;Wagner, Christa L.;Lieblich, Lawrence M.;Auerbach, Robert;Auerbach, Arleen D.;Wheelan, Sarah J.;Armanios, Mary
先天性角化不良症是一种由皮肤粘膜特征定义的端粒介导综合征。x连锁遗传模式占了一半的病例，并且被认为主要表现在儿童时期的骨髓衰竭。我们确定了两名男性先证者，他们在第50年出现特发性肺纤维化和癌症。他们的家谱显示出连续的受影响的世代。6名女性中有5名（83%）表现出先天性角化不良的粘膜皮肤特征，2名有伤口愈合并发症。常染色体显性端粒基因未出现突变，但外显子组测序显示x染色体DKC1基因出现新变异，预测保守残基p.s thr49ser和p.p pro409arg的错义突变。与端粒表型分离的变异，受影响的雌性是杂合子，表现出倾斜的x失活。端粒酶RNA水平在DKC1突变携带者的细胞中受损，与它们的致病作用一致。这些发现表明，具有杂合子DKC1突变的女性发生端粒表型的风险可能增加，有时可能与临床发病率相关。
Dyskeratosis congenita is a telomere-mediated syndrome defined by mucocutaneous features. The X-linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of dyskeratosis congenita, and two had wound-healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X-chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes showing skewed X-inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing telomere phenotypes that, at times, may be associated with clinical morbidity.
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DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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影响因子：
6.5
作者：
Knight, SW;Heiss, NS;Dokal, I
通讯作者：
Dokal, I
影响因子：
4.5
作者：
Alder JK;Cogan JD;Brown AF;Anderson CJ;Lawson WE;Lansdorp PM;Phillips JA 3rd;Loyd JE;Chen JJ;Armanios M
通讯作者：
Armanios M
影响因子：
30.8
作者：
Heiss, NS;Knight, SW;Dokal, I
通讯作者：
Dokal, I
DOI：
10.1073/pnas.0508124102
发表时间：
2005-11-01
影响因子：
11.1
作者：
Armanios, M;Chen, JL;Greider, CW
通讯作者：
Greider, CW