Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas
Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas
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DOI：
10.1007/s00439-008-0586-5
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发表时间：
2009-01-01
期刊：
影响因子：
5.3
通讯作者：
Jeffery, Steve
中科院分区：
文献类型：
--
作者：
Connell, F. C.;Ostergaard, P.;Jeffery, Steve
Milroy病(遗传性淋巴水肿I型，MIM 153100)是一种先天性起病的原发淋巴水肿病，常染色体显性遗传。该基因的突变，即血管内皮生长因子受体3，VEGFR3(Flt4)，已知会导致Milroy病，但VEGFR3突变在原发性淋巴水肿患者中的患病率尚不确定，更具体地说，在那些表型类似Milroy病的患者中。这项研究旨在解决这一问题，从而描绘出米尔罗伊病的表型。对52例原发性淋巴水肿患者进行了VEGFR3编码区突变分析。将患者分为有家族史的典型Milroy病(I组)、无家族史的典型Milroy病(II组)、非典型Milroy病(III组)和复杂性原发淋巴水肿组(IV组)。结果表明，通过严格的表型，检测到VEGFR3突变的可能性被优化。有家族史的典型米尔罗伊患者(组I)突变发生率为75%，如果阳性家族史不是诊断标准，突变发生率为68%。在米尔罗伊病中，阳性家族史并不是必须的。在具有非典型Milroy病表型的患者中检测到VEGFR3突变的可能性非常小(<；5%)。在22例突变阳性的患者中，发现了14个新的VEGFR3突变，其中2个位于外显子22，1个位于外显子17，证实这些外显子应包括在VEGFR3分析中。没有发现激活域以外的突变，这表明对这部分基因的分析对米尔罗伊病患者没有用处。对所有典型的Milroy病患者(组I和组II)进行了编码VEGFR3配体的VEGFC测序，没有发现突变。
Milroy disease (hereditary lymphoedema type I, MIM 153100) is a congenital onset primary lymphoedema with autosomal dominant inheritance. Mutations in the gene, vascular endothelial growth factor receptor 3, VEGFR3 (FLT4), are known to cause Milroy disease, but there is uncertainty about the prevalence of VEGFR3 mutations in patients with primary lymphoedema and more specifically in those with a phenotype that resembles Milroy disease. This study aims to address this issue and thereby delineate the Milroy disease phenotype. Fifty-two patients with primary lymphoedema were analysed for mutations in the coding regions of VEGFR3. Patients were divided into four groups: Typical Milroy disease with family history (group I), typical Milroy disease with no family history (group II), atypical Milroy disease (group III), and complex primary lymphoedema (group IV). Results demonstrated that with rigorous phenotyping the likelihood of detecting VEGFR3 mutations is optimised. Mutation prevalence is 75% in typical Milroy patients with a family history (group I) and 68% if positive family history is not a diagnostic criterion. A positive family history is not essential in Milroy disease. The likelihood of detecting VEGFR3 mutations in patients who have a phenotype which is not typical of Milroy disease is very small (< 5%). For the 22 mutation positive patients, 14 novel VEGFR3 mutations were identified, two of which were in exon 22 and one in exon 17, confirming that these exons should be included in VEGFR3 analysis. No mutations were found outside the kinase domains, showing that analysis of this part of the gene is not useful for Milroy disease patients. VEGFC, which encodes the ligand for VEGFR3, was sequenced in all patients with typical Milroy disease (groups I and II) and no mutations were identified.