Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia
Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia
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DOI：
10.1016/j.mrfmmm.2007.08.003
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发表时间：
2008-01-01
影响因子：
2.3
通讯作者：
Ozturk, Mehmet
中科院分区：
文献类型：
--
作者：
Alotaibi, Hani;Ricciardone, Marie D.;Ozturk, Mehmet
DNA错配修复（MMR）基因的杂合种系变异使个体易患遗传性非息肉病性结直肠癌。一些独立的报告表明，个体体质纯合子的MMR等位基因变异发展早发性血液恶性肿瘤往往与功能的神经纤维瘤病1型（NF 1）综合征。NF 1与MMR基因缺陷相关的遗传机制尚不完全清楚。我们在此报告，这种形式的NF I的儿童显示一个杂合NF 1基因突变（c.3721C > T），除了纯合MLH 1基因突变（c.676C > T），导致截断MLH 1蛋白（p.R226X）。父母没有显示NF 1功能，也没有NF 1突变。这种新的NF 1基因突变是复发性的，并预测了一个截短的神经纤维蛋白（p.R1241X）缺乏其GT3激活功能，以及所有C-末端定位的功能结构域。我们的研究结果表明，在有害的MMR变异纯合子个体中观察到的NF I疾病可能是由于伴随的NF 1基因突变。纯合子MLH 1和杂合子NF 1突变的存在下，在这里研究的儿童也提供了一个机制解释早发性恶性肿瘤，观察到在受影响的个人。它还提供了一个模型，在人类致癌遗传变异之间的合作。(c)2007 Elsevier B. V.保留所有权利。
Heterozygous germ-line variants of DNA mismatch repair (MMR) genes predispose individuals to hereditary non-polyposis colorectal cancer. Several independent reports have shown that individuals constitutionally homozygous for MMR allelic variants develop early onset hematological malignancies often associated to features of neurofibromatosis type 1 (NF1) syndrome. The genetic mechanism of NF1 associated to MMR gene deficiency is not fully known. We report here that a child with this form of NF I displays a heterozygous NF1 gene mutation (c.3721C > T), in addition to a homozygous MLH1 gene mutation (c.676C > T) leading to a truncated MLH1 protein (p.R226X). The parents did not display NF1 features nor the NF1 mutation. This new NF1 gene mutation is recurrent and predicts a truncated neurofibromin (p.R1241X) lacking its GTPase activating function, as well as all C-terminally located functional domains. Our findings suggest that NF I disease observed in individuals homozygous for deleterious MMR variants may be due to a concomitant NF1 gene mutation. The presence of both homozygous MLH1 and heterozygous NF1 mutation in the child studied here also provides a mechanistic explanation for early onset malignancies that are observed in affected individuals. It also provides a model for cooperation between genetic alterations in human carcinogenesis. (c) 2007 Elsevier B.V. All rights reserved.