6 NOVEL MUTATIONS IN THE ENDOGLIN GENE IN HEREDITARY HEMORRHAGIC TELANGIECTASIA TYPE-1 SUGGEST A DOMINANT-NEGATIVE EFFECT OF RECEPTOR FUNCTION
6 NOVEL MUTATIONS IN THE ENDOGLIN GENE IN HEREDITARY HEMORRHAGIC TELANGIECTASIA TYPE-1 SUGGEST A DOMINANT-NEGATIVE EFFECT OF RECEPTOR FUNCTION
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DOI：
10.1093/hmg/4.10.1983
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发表时间：
1995-10-01
影响因子：
3.5
通讯作者：
MARCHUK, DA
中科院分区：
文献类型：
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作者：
MCALLISTER, KA;BALDWIN, MA;MARCHUK, DA
遗传性出血性毛细血管扩张症或Osler-Rendu-Weber（ORW）病是一种常染色体显性遗传疾病，以多系统血管发育不良为特征。一些家族的遗传连锁被建立到染色体9 q34（0 RW 1）（1，2），但遗传异质性被证明与一些家族的鉴定明确不与该位点连锁（2-5）。肺动静脉畸形（PAVM）的易感性似乎在0 RW 1家族中分离（3-5）。最近，内皮糖蛋白（ENG），一种转化生长因子P（TGF-β）结合蛋白，被鉴定为0 RW 1基因座，在受影响的个体中鉴定出三个独立的突变（6）。我们现在报告了另外6个内皮糖蛋白突变，包括先前描述的0 RW 1家族中的2个。观察到的突变类型及其在某些外显子中的位置，以及其他外显子中突变的明显缺失或代表性不足，表明受体功能障碍的显性负性机制是这种疾病的分子基础。在初始突变筛查中使用的一组80个DNA样本包括来自先前与9 q34相关的9个家族的受影响个体（1，3-5）。其余71个样本中的大多数来自有PAVM参与史的家族，增加了每个个体携带独立内皮糖蛋白突变的可能性。如前所述（6），设计引物以扩增14个内皮糖蛋白外显子中的11个，尽管重新设计了一些引物对以产生更小的扩增产物。经修订的引物序列和反应条件可通过GenBank数据库以条目GOO-553-288获得。进行异源双链体分析，并如前所述直接对PCR产物进行测序（6）。表1列出了迄今为止的内皮糖蛋白突变总结，包括三个先前发表的突变（6）。每种突变仅见于分析的160多条染色体中的一条染色体。当有额外的家族成员时，突变与疾病表型共分离。
Hereditary Hemorrhagic Telangiectasia or Osler-Rendu-Weber (ORW) disease is an autosomal dominant disorder characterized by multisystemic vascular dysplasia. Genetic linkage for some families was established to chromosome 9q34 (0RW1)(1, 2) but genetic heterogeneity was demonstrated with the identification of some families clearly not linked to this locus (2-5). A predisposition for the development of pulmonary arteriovenous malformations (PAVMs) appears to segregate in 0RW1 families (3-5). Recently, endoglin (ENG), a transforming growth factor P (TGF-p) binding protein, was identified as the 0RW1 locus, with three independent mutations identified in affected individuals (6). We now report an additional six endoglin mutations including two in previously described 0RW1 families. The type of mutations observed and their location in certain exons, with the apparent absence or under-representation of mutations in other exons, suggests a dominant-negative mechanism of receptor malfunctioning as the molecular basis of this disorder.A panel of 80 DNA samples used in the initial mutation screen included affected individuals from nine families previously linked to 9q34 (1, 3-5). Most of the remaining 71 samples were from families with a history of PAVM involvement, increasing the likelihood that each individual would harbor an independent endoglin mutation. Primers were designed to amplify 11 of the 14 endoglin exons as previously described (6), although some primer pairs were redesigned to create smaller amplification products. The revised primer sequences and reaction conditions are available through GenBank Databank as entry GOO-553-288. Heteroduplex analysis was performed and PCR products were directly sequenced as previously described (6). Table 1 catalogs the endoglin mutation summary to date, including three previously published mutations (6). Each of the mutations was seen only in a single chromosome in over 160 total chromosomes analyzed. Where additional family members were available, the mutations were shown to co-segregate with the disease phenotype.