Data_Sheet_3_Clinical Manifestations of Alport Syndrome-Diffuse Leiomyomatosis Patients With Contiguous Gene Deletions in COL4A6 and COL4A5.PDF

Alport syndrome-diffuse leiomyomatosis is a rare type of X-linked Alport syndrome resulting from contiguous deletions of 5′ exons of COL4A5 and COL4A6. Studies have suggested that the occurrence of diffuse leiomyomatosis is associated with the characteristic localisation of the COL4A6 gene deletion break point. An electronic database was searched for all studies accessing AS-DL to analyze the clinical characteristics, gene deletion break points of patients with AS-DL, and the pathogenesis of AS-DL. It was found that the proportion of de novo mutations of AS-DL was significantly higher in female probands than male probands (78 vs. 44%). Female patients with AS-DL had a mild clinical presentation. The incidence of proteinuria and ocular abnormalities was much lower in female probands than in male probands, and there was generally no sensorineural hearing loss or chronic kidney disease (CKD), which progressed to Stage 3 in female probands. The contiguous deletion of the 5' exons of COL4A5 and COL4A6, with the break point within the intron 3 of COL4A6, was the critical genetic defect causing AS-DL. However, the pathogenesis of characteristic deletion of COL4A6 that contributes to diffuse leiomyomatosis is still unknown. In addition, characteristic contiguous deletion of COL4A5 and COL4A6 genes in AS-DL may be related to transposed elements (TEs).

奥尔波特综合征-弥漫性平滑肌瘤病（Alport syndrome-diffuse leiomyomatosis，以下简称AS-DL）是一类罕见的X连锁奥尔波特综合征（X-linked Alport syndrome），由COL4A5与COL4A6基因的5'端外显子连续缺失所导致。已有研究表明，弥漫性平滑肌瘤病的发生与COL4A6基因缺失断裂点的特征性定位密切相关。本研究检索了所有纳入AS-DL相关研究的电子数据库，以分析AS-DL患者的临床特征、基因缺失断裂点及该病的发病机制。研究发现，AS-DL女性先证者的新发突变比例显著高于男性先证者（78% vs 44%）。AS-DL女性患者临床表型相对轻微，其蛋白尿与眼部异常的发生率远低于男性先证者，且通常无伴感音神经性听力损失；即便罹患慢性肾脏病（CKD），也极少进展至3期。COL4A5与COL4A6基因5'端外显子的连续缺失，且断裂点位于COL4A6基因内含子3区域，是导致AS-DL的关键遗传缺陷。然而，COL4A6特征性缺失引发弥漫性平滑肌瘤病的具体发病机制仍未阐明。此外，AS-DL患者中COL4A5与COL4A6基因的特征性连续缺失，可能与转座元件（transposed elements, TEs）存在关联。