Harrison R E, Flanagan J A, Sankelo M, Abdalla S A, Rowell J, Machado R D, Elliott C G, Robbins I M, Olschewski H, McLaughlin V, Gruenig E, Kermeen F, Halme M, Räisänen-Sokolowski A, Laitinen T, Morrell N W, Trembath R C
Division of Medical Genetics, University of Leicester, Leicester, UK.
J Med Genet. 2003 Dec;40(12):865-71. doi: 10.1136/jmg.40.12.865.
Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension.
To investigate kindreds presenting with both pulmonary hypertension and HHT.
Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling.
Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN.
The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.
转化生长因子β（TGFβ）受体成分内皮糖蛋白（ENDOGLIN）和激活素受体样激酶1（ALK-1）的突变会导致常染色体显性血管疾病遗传性出血性毛细血管扩张症（HHT）。II型受体骨形态发生蛋白受体2（BMPR2）的杂合突变是家族性原发性肺动脉高压的基础。
研究同时患有肺动脉高压和HHT的家族。
由五个国家的专业肺动脉高压中心确定先证者和家族。对ALK-1、ENDOGLIN和BMPR2进行DNA序列分析。通过在牛主动脉内皮细胞（BAEC）和人宫颈癌细胞（HeLa）中异源过表达突变体构建体来研究细胞定位。通过比较分析和计算机建模评估一种新的序列变异的影响。
对11名先证者的分子分析确定了8个ALK-1错义突变，其中1个在两个家族中观察到。突变位于ALK-1基因的外显子5至10内。大多数ALK-1突变体构建体似乎保留在细胞质中的内质网内。一种新的GS结构域突变在过表达时到达细胞表面，但预计会因关键氢键的丧失而破坏构象变化。在ENDOGLIN中鉴定出两个新的错义突变。
肺动脉高压与HHT的关联确定了一种重要的疾病并发症，并且在ALK-1受体信号传导缺陷的受试者中似乎最为常见。未来的研究应集中于对由导致遗传性肺血管疾病的ALK-1和BMPR2突变破坏的常见细胞途径进行详细的分子分析。
