A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome

Yoshinori Sato, Hiroyasu Tsukaguchi, Hiroyuki Morita, Koichiro Higasa, Mai Thi Nhu Tran, Michito Hamada, Toshiaki Usui, Naoki Morito, Shoichiro Horita, Takao Hayashi, Junko Takagi, Izumi Yamaguchi, Huan Thanh Nguyen, Masayo Harada, Kiyoko Inui, Yuichi Maruta, Yoshihiko Inoue, Fumihiko Koiwa, Hiroshi Sato, Fumihiko MatsudaShinya Ayabe, Seiya Mizuno, Fumihiro Sugiyama, Satoru Takahashi, Ashio Yoshimura

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)396-407
Number of pages12
JournalKidney international
Issue number2
Publication statusPublished - 2018 Aug


  • FSGS
  • kidney development
  • nephrotic syndrome
  • podocyte
  • transcriptional regulation

ASJC Scopus subject areas

  • Nephrology


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