A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome
A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome
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DOI：
10.1016/j.kint.2018.02.025
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发表时间：
2018-08-01
影响因子：
19.6
通讯作者：
Yoshimura, Ashio
中科院分区：
文献类型：
--
作者：
Sato, Yoshinori;Tsukaguchi, Hiroyasu;Yoshimura, Ashio
局灶节段性肾小球硬化（FSGS）是儿童和成人终末期肾病的主要原因。遗传因素显著有助于早发性FSGS，但大多数成人病例的病因仍不清楚。表现出肾外表现的单基因综合征FSGS的遗传学研究揭示了基因在足细胞和其他细胞谱系发育中的意想不到的生物学作用。为了帮助定义这些角色，我们研究了两个患有与杜安退缩综合征相关的FSGS的无血缘关系的家庭，其特征是由于脑神经畸形导致水平眼球运动受损。4例患者均在1 ~ 20岁时发生FSGS和Duane退缩综合征，表现为外展受限伴地球仪退缩和内收时睑裂变窄。外展神经发育不良和听力障碍发生在严重受影响的个人。遗传分析显示，受影响的个人港口一个罕见的杂合取代（p.Leu239Pro）在MAFB，亮氨酸拉链转录因子。用培养的单核细胞进行的荧光素酶测定表明，取代显著降低了F4/80启动子（已知的MAFB识别元件）的反式激活。此外，免疫组织化学表明患者足细胞中MAFB表达减少。结构建模表明，DNA结合结构域中的p.Leu239Pro取代可能会干扰相邻锌指的稳定性。最后，p.Leu239Pro新生小鼠的足细胞分化受损。因此，MAFB突变损害足细胞、外展神经元和内耳的发育和/或维持。MAFB和这些发育器官中的调控元件之间的相互作用可能是基于时空要求的高度特异性的。
Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease in children and adults. Genetic factors significantly contribute to early-onset FSGS, but the etiologies of most adult cases remain unknown. Genetic studies of monogenic syndromic FSGS exhibiting extra-renal manifestations have uncovered an unexpected biological role for genes in the development of both podocytes and other cellular lineages. To help define these roles, we studied two unrelated families with FSGS associated with Duane Retraction Syndrome, characterized by impaired horizontal eye movement due to cranial nerve malformation. All four affected individuals developed FSGS and Duane Retraction Syndrome in their first to second decade of life, manifested as restricted abduction together with globe retraction and narrowed palpebral fissure on attempted adduction. Hypoplasia of the abducens nerves and hearing impairment occurred in severely affected individuals. Genetic analyses revealed that affected individuals harbor a rare heterozygous substitution (p.Leu239Pro) in MAFB, a leucine zipper transcription factor. Luciferase assays with cultured monocytes indicated that the substitution significantly reduced transactivation of the F4/80 promoter, the known MAFB recognition element. Additionally, immunohistochemistry indicated reduced MAFB expression in the podocytes of patients. Structural modeling suggested that the p.Leu239Pro substitution in the DNA-binding domain possibly interferes with the stability of the adjacent zinc finger. Lastly, podocytes in neonatal mice with p.Leu239Pro displayed impaired differentiation. Thus, MAFB mutations impair development and/or maintenance of podocytes, abducens neurons and the inner ear. The interactions between MAFB and regulatory elements in these developing organs are likely highly specific based on spatiotemporal requirements.