Further delineation of Loeys-Dietz syndrome type 4 in a family with mild vascular involvement and a TGFB2 splicing mutation.
Further delineation of Loeys-Dietz syndrome type 4 in a family with mild vascular involvement and a TGFB2 splicing mutation.
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DOI：
10.1186/s12881-014-0091-8
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发表时间：
2014-08-28
影响因子：
--
通讯作者：
Colombi M
中科院分区：
文献类型：
--
作者：
Ritelli M;Chiarelli N;Dordoni C;Quinzani S;Venturini M;Maroldi R;Calzavara-Pinton P;Colombi M
Loeys-Dietz 综合征 (LDS) 是一种罕见的常染色体显性遗传疾病，其特征是胸主动脉瘤和夹层以及广泛的全身结缔组织受累。 LDS 1 至 4 型由 TGF-β 信号通路基因突变引起：编码 TGF-β 受体的 TGFBR1 和 TGFBR2（LDS1 和 LDS2）、编码 TGF-β 受体胞质效应子（LDS3）的 SMAD3 和编码 TGF-β2 配体（LDS4）的 TGFB2。 LDS4 代表 LDS 谱系中最温和的一端，因为动脉瘤通常在四十岁左右观察到，并且疾病的进展速度比其他形式慢。我们报告了一个 LDS4 意大利家族的临床和分子研究结果。基因检测包括通过桑格测序进行 TGFBR1、TGFBR2、SMAD3 和 TGFB2 分析。为了验证所鉴定的剪接突变的效果，进行了RT-PCR分析。先证者是一名57岁女性，表现出高腭、悬雍垂发育不全、容易瘀伤、关节过度活动、慢性疼痛、脊柱侧弯、多发性复发性疝气、硬脑膜扩张和二尖瓣脱垂。磁共振血管造影显示颈动脉、椎动脉、脑动脉和节段性肺动脉迂曲和扩张。从未发生动脉瘤和夹层。她 39 岁和 34 岁的女儿均出现不同程度的肌肉骨骼受累。分子分析揭示了 TGFB2 基因中新的 c.839-1G>A 剪接位点突变。该突变激活外显子 6 中的一个隐秘剪接受体位点，导致移码、提前终止密码子和单倍体不足 (p.Gly280Aspfs*41)。我们的数据证实，TGFB2 基因的功能丧失突变并不总是导致侵袭性血管表型，并且关节和骨骼体征很普遍，因此表明在没有血管事件的情况下，对于 LDS 和相关疾病的稀疏体征的患者必须考虑 LDS4。
The Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disorder characterized by thoracic aortic aneurysm and dissection and widespread systemic connective tissue involvement. LDS type 1 to 4 are caused by mutations in genes of the TGF-β signaling pathway: TGFBR1 and TGFBR2 encoding the TGF-β receptor (LDS1 and LDS2), SMAD3 encoding the TGF-β receptor cytoplasmic effector (LDS3), and TGFB2 encoding the TGF-β2 ligand (LDS4). LDS4 represents the mildest end of the LDS spectrum, since aneurysms are usually observed in fourth decade and the progression of the disease is slower than in the other forms. We report the clinical and molecular findings of an LDS4 Italian family. Genetic testing included TGFBR1, TGFBR2, SMAD3, and TGFB2 analysis by Sanger sequencing. In order to verify the effect of the identified splice mutation, RT-PCR analysis was performed. The proband, a 57-year-old woman, showed high palate, hypoplasic uvula, easy bruising, joint hypermobility, chronic pain, scoliosis, multiple relapsing hernias, dural ectasia, and mitral valve prolapse. Magnetic resonance angiography revealed tortuosity and ectasia of carotid, vertebral, cerebral, and segmental pulmonary arteries. Arterial aneurysm and dissection never occurred. Her 39- and 34-year-old daughters presented with a variable degree of musculoskeletal involvement. Molecular analysis disclosed the novel c.839-1G>A splice site mutation in the TGFB2 gene. This mutation activates a cryptic splice acceptor site in exon 6 leading to frameshift, premature termination codon and haploinsufficiency (p.Gly280Aspfs*41). Our data confirm that loss-of-function mutations in TGFB2 gene do not always lead to aggressive vascular phenotypes and that articular and skeletal signs are prevalent, therefore suggesting that LDS4 must be considered in patients with sparse signs of LDS and related disorders also in the absence of vascular events.
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影响因子：
3.7
作者：
Drera, Bruno;Ritelli, Marco;Colombi, Marina
通讯作者：
Colombi, Marina
影响因子：
5.2
作者：
Leutermann, Ruth;Sheikhzadeh, Sara;Rosenberger, Georg
通讯作者：
Rosenberger, Georg
影响因子：
3.5
作者：
Rodrigues, V. J.;Elsayed, S.;Yousem, D. M.
通讯作者：
Yousem, D. M.
影响因子：
30.8
作者：
van de laar, Ingrid M. B. H.;Oldenburg, Rogier A.;Bertoli-Avella, Aida M.
通讯作者：
Bertoli-Avella, Aida M.
影响因子：
30.8
作者：
Boileau, Catherine;Guo, Dong-Chuan;Hanna, Nadine;Regalado, Ellen S.;Detaint, Delphine;Gong, Limin;Varret, Mathilde;Prakash, Siddharth K.;Li, Alexander H.;d'Indy, Hyacintha;Braverman, Alan C.;Grandchamp, Bernard;Kwartler, Callie S.;Gouya, Laurent;Santos-Cortez, Regie Lyn P.;Abifadel, Marianne;Leal, Suzanne M.;Muti, Christine;Shendure, Jay;Gross, Marie-Sylvie;Rieder, Mark J.;Vahanian, Alec;Nickerson, Deborah A.;Michel, Jean Baptiste;Jondeau, Guillaume;Milewicz, Dianna M.
通讯作者：
Milewicz, Dianna M.