Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis
Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis
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DOI：
10.1073/pnas.96.4.1609
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发表时间：
1999-02-16
影响因子：
11.1
通讯作者：
Ma, YS
中科院分区：
文献类型：
--
作者：
Longley, BJ;Metcalfe, DD;Ma, YS
人类肥大细胞增多症的特征是肥大细胞增多。它通常作为一种散发性疾病发生，在儿童中通常是短暂且有限的，而在成人中是持续性或进行性的。 c-KIT 原癌基因编码 KIT，一种酪氨酸激酶，是肥大细胞生长因子的受体。由于突变的 KIT 可以转化细胞，我们检测了 22 名散发性肥大细胞增多症患者和 3 名家族性肥大细胞增多症患者皮损中的 c-KIT。所有成人散发性肥大细胞增多症患者均在密码子 816 处出现体细胞 c-KIT 突变，导致缬氨酸取代天冬氨酸并自发激活肥大细胞生长因子受体（P = 0.0001）。患有临床异常疾病的四名儿科发病病例的子集也有密码子 816 激活突变，用缬氨酸、酪氨酸或苯丙氨酸取代天冬氨酸。典型的儿科患者缺乏 816 个突变，但有限的测序显示，六分之三的患者中有一个新的显性失活突变，用赖氨酸取代了第 839 位的谷氨酸，这是一个潜在的盐桥位点，该突变高度 在受体酪氨酸激酶中保守。在三名家族性肥大细胞增多症患者的整个编码区中未发现c-KIT突变。我们得出结论，c-KIT体细胞突变在KIT的816位取代缬氨酸是散发性成人肥大细胞增多症的特征，并可能导致这种疾病。在明显面临广泛或持续性疾病风险的儿童中也发现了导致肥大细胞生长因子受体激活的类似突变。相反，典型的儿科肥大细胞增多症患者缺乏这些突变，并且可能表达失活的 c-KIT 突变。然而，家族性肥大细胞增多症可能在没有 c-KIT 编码突变的情况下发生。
Human mastocytosis is characterized by increased mast cells. It usually occurs as a sporadic disease that is often transient and limited in children and persistent or progressive in adults. The c-KIT protooncogene encodes KIT, a tyrosine kinase that is the receptor for mast cell growth factor. Because mutated KIT can transform cells, we examined c-KIT in skin lesions of 22 patients with sporadic mastocytosis and 3 patients with familial mastocytosis, All patients with adult sporadic mastocytosis had somatic c-KIT mutations in codon 816 causing substitution of valine for aspartate and spontaneous activation of mast cell growth factor receptor (P = 0.0001). A subset of four pediatric onset cases with clinically unusual disease also had codon 816 activating mutations substituting valine, tyrosine, or phenylalanine for aspartate, Typical pediatric patients lacked 816 mutations, but limited sequencing showed three of six had a novel dominant inactivating mutation substituting lysine for glutamic acid in position 839, the site of a potential salt bridge that is highly conserved in receptor tyrosine kinases. No c-KIT mutations were found in the entire coding region of three patients with familial mastocytosis, We conclude that c-KIT somatic mutations substituting valine in position 816 of KIT are characteristic of sporadic adult mastocytosis and may cause this disease. Similar mutations causing activation of the mast cell growth factor receptor are found in children apparently at risk for extensive or persistent disease. In contrast, typical pediatric mastocytosis patients lack these mutations and may express inactivating c-KIT mutations. Familial mastocytosis, however, may occur in the absence of c-KIT coding mutations.