c-kit mutations in patients with childhood-onset mastocytosis and genotype-phenotype correlation
c-kit mutations in patients with childhood-onset mastocytosis and genotype-phenotype correlation
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DOI：
10.1016/s1525-1578(10)60552-1
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发表时间：
2005-05-01
影响因子：
4.1
通讯作者：
Kaneko, F
中科院分区：
文献类型：
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作者：
Yanagihori, H;Oyama, N;Kaneko, F
肥大细胞增多症代表由c-kit基因的功能获得性突变引起的肥大细胞造血祖细胞的克隆性增殖。c-kit突变的异质性可能导致难以表征疾病的基因型-表型相关性。我们的目标是分析一组儿童期皮肤肥大细胞增多症患者与成人期皮肤肥大细胞增多症患者的致病性c-kit突变，并将其与临床表现相关联。我们对16例非家族性日本惰性皮肤肥大细胞增多症患者（12例儿童期发病，4例成人期发病）的基因组DNA样本进行聚合酶链反应和直接测序，以寻找最常见的c-kit突变密码子816、560、820和839。相当数量的患者有错义密码子816突变（10/12的儿童期发病组，83.3%; 4/4的成人期发病组，100%）。最常见的突变是Asp 816 Val（9/16，64.3%），其次是Asp 816 Phe（5/16，35.7%）。此外，Asp 816 Phe突变的儿童发生皮肤肥大细胞增多症的年龄早于Asp 816 Val突变的儿童（平均发病年龄分别为1.3个月和5.9个月; P = 0.068）。在我们的队列中没有发现其他突变变异。总之，我们证实了两个不同的c-kit突变，Asp 816 Val和Asp 816 Phe，在儿童期发病的皮肤肥大细胞增多症患者的高发病率。我们的研究结果为常见的c-kit突变提供了新的见解，这可能有助于疾病的不同临床病程。
Mastocytosis represents a clonal proliferation of mast cell hematopoietic progenitors caused by gain-of-function mutations of the c-kit gene. The heterogeneity of c-kit mutations may have contributed to difficulties in characterizing genotype-phenotype correlation of the disease. Our goal was to analyze a set of reported pathogenic c-kit mutations in patients with childhood-onset cutaneous mastocytosis, in comparison with those with adult-onset disease, and to correlate these with clinical presentation. We performed polymerase chain reaction and direct sequencing using genomic DNA samples from 16 nonfamilial Japa nese patients with indolent cutaneous mastocytosis (12 with childhood-onset disease and 4 with adult-onset disease) to look for the most common c-kit mutations at codons 816, 560, 820, and 839. A substantial number of patients had missense codon 816 mutations (10 of 12 in the childhood-onset group, 83.3%; and 4 of 4 in the adult-onset group, 100%). The most common mutation was Asp816Val (9 of 16, 64.3%) followed by Asp816Phe (5 of 16, 35.7%). Moreover, children with the Asp816Phe mutation developed cutaneous mastocytosis at an earlier age as compared to those with the Asp816Val mutation (mean age of onset, 1.3 months versus 5.9 months, respectively; P = 0.068). No other mutation variations were found in our cohort. In summary, we confirmed a high incidence of two distinct c-kit mutations, Asp816Val and Asp816Phe, in patients with childhood-onset cutaneous mastocytosis. Our results provide new insights into common c-kit mutations, which may contribute to different clinical courses of the disease.