Deletion mapping in Alport syndrome and Alport syndrome-diffuse leiomyomatosis reveals potential mechanisms of visceral smooth muscle overgrowth.
Deletion mapping in Alport syndrome and Alport syndrome-diffuse leiomyomatosis reveals potential mechanisms of visceral smooth muscle overgrowth.
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DOI：
10.1002/humu.9191
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发表时间：
2003-11-01
期刊：
影响因子：
3.9
通讯作者：
Segal, Yoav
中科院分区：
文献类型：
--
作者：
Thielen, Beth K;Barker, David F;Segal, Yoav
弥漫性平滑肌瘤病与遗传性肾病阿尔波特综合征有关，其特征是呼吸道、胃肠道和女性生殖道内脏平滑肌过度生长。尽管已知 IV 型胶原蛋白基因 COL4A5 和 COL4A6（在染色体 Xq22 上配对）的部分缺失会导致弥漫性平滑肌瘤病，但 IV 型胶原蛋白功能丧失并不能解释平滑肌过度生长。为了进一步阐明致病机制，我们对阿尔波特综合征-弥漫性平滑肌瘤病或单纯阿尔波特综合征患者的新缺失进行了表征。患有阿尔波特综合征-弥漫性平滑肌瘤病的女性中的 27.6-kb 缺失以迄今为止描述的最近端（即最 5'）COL4A5 断点为标志。通过将此缺失与此处和之前描述的其他缺失进行比较，我们定义了一个最小重叠区域，长度仅为 4.2 kb，并包含 COL4A5-COL4A6 近端启动子，其缺失会导致平滑肌过度生长。仅患有 Alport 综合征的男性中的一个新缺失长度>1.4 Mb，完全包含 COL4A5 和 COL4A6 以及邻近基因。我们假设弥漫性平滑肌瘤病中 4.2 kb 区域的丢失会导致邻近基因的失调，从而导致平滑肌过度生长。删除邻近基因本身可能会提供针对这种情况的保护。
Diffuse leiomyomatosis is associated with the inherited kidney disease Alport syndrome, and characterized by visceral smooth muscle overgrowth within the respiratory, gastrointestinal and female reproductive tracts. Although partial deletions of the type IV collagen genes COL4A5 and COL4A6, paired head-to-head on chromosome Xq22, are known to cause diffuse leiomyomatosis, loss of function for type IV collagen does not explain smooth muscle overgrowth. To further clarify pathogenic mechanisms, we have characterized novel deletions in patients with Alport syndrome-diffuse leiomyomatosis or Alport syndrome alone. A 27.6-kb deletion, in a female with Alport syndrome-diffuse leiomyomatosis, is marked by the most proximal, i.e. most 5', COL4A5 breakpoint described to date. By comparing this deletion to others described here and previously, we have defined a minimal overlap region, only 4.2 kb in length and containing the COL4A5-COL4A6 proximal promoters, loss of which contributes to smooth muscle overgrowth. A novel deletion in a male with Alport syndrome alone is>1.4 Mb in length, encompassing COL4A5 and COL4A6 entirely, as well as neighboring genes. We postulate that loss of the 4.2-kb region in diffuse leiomyomatosis causes misregulation of neighboring genes, contributing to smooth muscle overgrowth. Deletion of the neighboring genes themselves may afford protection from this condition.