Genetics of Fibromuscular Dysplasia

Ehlers-Danlos综合征（EDS）是一组异质性结缔组织遗传性疾病，其特征在于关节、皮肤和血管异常。血管夹层和动脉瘤是由COL 3A 1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TGF β R2或TGF β R1突变引起。 我们确定了一组没有COL 3A 1、TGF β R2或TGF β R1突变的患者，他们表现为夹层和动脉瘤以及狭窄病变，经病理学或放射学诊断为纤维肌性发育不良（FMD）。还存在EDS的不同特征，如萎缩性瘢痕、天鹅绒般柔软或有弹性的皮肤、由高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、胸畸形、扁平足和脊柱侧凸。一些患者有血管事件导致过早死亡的家族史，以及与常染色体显性遗传模式相符的关节和皮肤异常的家族史。FMD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。我们的研究结果表明，有一个独特的变异EDS，独立于VEDS和Loeys-Dietz综合征，FMD作为一个临床特征，除了皮肤和关节异常。 鉴于与TGF β受体突变引起的疾病的相似性，认为FMD是由同一途径中另一个基因的种系突变引起的假设。与BartLoeys博士合作，使用直接组织免疫化学方法研究了FMD患者中TGF β途径的紊乱。在患者样品的子集中观察到pSMAD 2水平增加。与TGF β途径有关的结果正在利用成纤维细胞系中的蛋白质印迹技术进行验证。 为了鉴定与FMD表型相关的基因，在方案2003-086中鉴定并招募了60名患有FMD的患者的初始队列，并且与Singleton博士合作使用具有HumanCNV 370-Duo BeadChips和HumanHap 550 BeadChips的Illumina平台完成了全基因组关联研究。结果表明与多个区域1p35.3、3q 24、3q 28、5p14.3、6p25.3、8p23.2、10p12.1、12q13.13、17q21.2和18p11.22连锁。根据初步结果，估计再增加90个样本将有助于缩小联系区域。患者招募现已完成，全基因组关联的第二阶段正在进行中。 我们还与Jennifer货车Eyk博士合作，积极研究了FMD患者血浆样本中疾病活动的生物标志物，并将这些结果与未受影响的对照组和受其他疾病（如马凡氏综合征和血管EDS）影响的患者进行了比较。初步结果表明，CRP，iCAM和vCAM在FMD中显著升高，与对照组相比。血清淀粉样蛋白α（SAA）与疾病活动性相关。FMD患者的循环TGF β 1水平升高，表明TGFB通路紊乱，用氯沙坦或其他调节该通路的血管紧张素受体阻断剂治疗可能对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.