Genetics of Fibromuscular Dysplasia

Ehler Danlos综合征(EDS)是一组以关节、皮肤和血管异常为特征的异质性结缔组织遗传性疾病。血管夹层和动脉瘤是由COL3A1突变引起的血管型EDS(VEDS)的主要特征。Loeys-Dietz综合征是一种密切相关的表型，由TGFbetaR2或TGFbetaR1突变引起。 我们已经确定了一组没有COL3A1、TGFbetaR2或TGFbetaR1突变的患者，他们表现为夹层和动脉瘤以及狭窄病变，经病理或放射学诊断为纤维肌肉发育不良(FMD)。EDS的不同特征，如萎缩的疤痕，天鹅绒或有弹性的皮肤，高Beighton评分证明的关节过度活动，关节脱位史，子宫脱垂，关节疼痛，胸骨畸形，扁平肌腱和脊柱侧弯也存在。其中几名患者有因血管事件过早死亡的家族史，以及符合常染色体显性遗传模式的关节和皮肤异常家族史。口蹄疫的病因被认为是异质性的，遗传和环境因素被认为是可能的贡献者。我们的发现表明，除了皮肤和关节异常外，还有一种明显的EDS变种，与VEDS和Loeys-Dietz综合征不同，FMD是一种临床特征。 考虑到与转化生长因子β受体突变引起的疾病相似，人们认为FMD是由同一途径中另一基因的胚系突变引起的。在Bart Loeys博士的合作下，使用直接组织免疫化学方法研究了口蹄疫患者中转化生长因子β途径的紊乱。在部分患者样本中可以看到pSMAD2水平的增加。在成纤维细胞系中，与转化生长因子β途径有关的结果正在利用Western blotting技术进行验证。 为了确定与口蹄疫表型相关的基因(S)，在2003-086年方案中确定并登记了60名口蹄疫患者的初始队列，并与Singleton博士合作，使用Illumina平台与HumanCNV370-Duo BeadChips和HumanHap550 BeadChips合作完成了全基因组关联研究。结果表明，1p35.3、3q24、3q28、5p14.3、6p25.3、8p23.2、10p12.1、12q13.13、17q21.2和18p11.22与多个区域连锁。根据初步结果，估计额外的90个样本将用于缩小连锁区域。患者招募现在已经完成，整个基因组关联的第二阶段正在进行中。 我们还积极研究了FMD患者血浆样本中疾病活动的生物标志物，并与未受影响的对照组以及与Jennifer Van Eyk博士合作的其他疾病患者(如马凡综合征和血管EDS)进行了比较。初步结果显示，与对照组相比，FMD患者的CRP、ICAM和VCAM显著升高。血清淀粉样蛋白α(SAA)与疾病活动性相关。FMD患者循环中的TGFbeta1水平升高，提示TGFb途径紊乱，使用调节该途径的氯沙坦或其他血管紧张素受体阻滞剂的治疗可能对FMD患者的治疗有益。

The Ehlers Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue characterized by joint, skin and vascular abnormalities. Vascular dissections and aneurysms are a cardinal feature of the vascular form of EDS (VEDS) caused by mutations in COL3A1. Loeys-Dietz syndrome, a closely related phenotype, is caused by mutations in TGFbetaR2 or TGFbetaR1. We have identified a group of patients without mutations in COL3A1, TGFbetaR2 or TGFbetaR1 who presented with dissections and aneurysms as well as stenotic lesions with a diagnosis of fibromuscular dysplasia (FMD) by pathology or radiology. Varying features of EDS such as atrophic scars, velvety or stretchy skin, joint hypermobility as evidenced by a high Beighton score, history of articular dislocations, uterine prolapse, joint pain, pectus deformities, pes planus and scoliosis were also present. Several of the patients had a family history of premature death from vascular events, as well as a family history of joint and skin abnormalities compatible with an autosomal dominant inheritance pattern. The etiology of FMD is thought to be heterogeneous, with genetic and environmental factors proposed as possible contributors. Our findings suggest that there is a distinct variant of EDS, separate from the VEDS and Loeys-Dietz syndrome, with FMD as a clinical feature in addition to the skin and joint abnormalities. Given the similarities with the disorders caused by mutations in receptors of TGFbeta, the hypothesis was entertained that FMD is caused by germline mutations in another gene in the same pathway. Derangements of the TGFbeta pathway were investigated in the FMD patients using direct tissue immunochemical approach in collaboration with Dr. Bart Loeys. Increased levels of pSMAD2 was seen in a subset of patient samples. The results pertaining to the TGFbeta pathway are being verified utilizing Western blotting techniqueds in fibroblast lines. To identify gene(s) that are associated with the FMD phenotype, an initial cohort of 60 patients with FMD was identified and enrolled in protocol 2003-086, and a whole genome association study was completed in collaboration with, Dr. Singleton using the Illumina Platform with HumanCNV370-Duo BeadChips and HumanHap550 BeadChips. The results indicate linkage to multiple regions 1p35.3, 3q24, 3q28, 5p14.3, 6p25.3, 8p23.2, 10p12.1, 12q13.13, 17q21.2, and 18p11.22. Based on the initial results, it was estimated that 90 additional samples would serve to narrow down the linkage regions. The patient recruitment is now complete and the second phase of the whole genome association is underway. We have also actively investigated biomarkers of disease activity in plasma samples from FMD patients with FMD and have compared these results to unaffected controls and to patients affected with other disorders such as Marfan syndrome and Vascular EDS in collaboration with Dr. Jennifer Van Eyk. Initial results indicate that CRP, iCAM and vCAM are significantly elevated in FMD as compared to controls. Serum Amyloid Alpha (SAA) shows correlations with disease activity. Circulating TGFbeta1 levels are elevated in FMD indicating derangement of the TGFB pathway, and treatment with losartan or other angiotensin receptor blockers that modulate the pathway may be of benefit in the treatment of patients suffering from FMD.