PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation.
PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation.
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DOI：
10.1242/dmm.049977
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发表时间：
2023-04-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
手足分裂畸形(SHFM)是一种罕见的伴有手指和/或脚趾裂伤的肢体畸形。对于许多人来说，遗传病因尚不清楚。通过全外显子组和靶向测序，我们检测到编码转录因子PRDM1的基因中有三个新的变异，它们从头开始在SHFM家族中出现或与表型分离。PRDM1是肢体发育所必需的；然而，它的作用尚不清楚，也不清楚PRDM1变体如何影响蛋白质功能。通过斑马鱼瞬时和稳定的过表达挽救实验，我们发现这些突变体破坏了富含脯氨酸/丝氨酸和DNA结合的锌指结构域，导致了显性-负效应。通过基因表达分析、RNA测序和在分离的胸鳍细胞中切割和运行，我们证明Prdm1a直接与鳍诱导、生长和前后模式所需的基因结合并调节，如fgfr1a、dlx5a、dlx6a和smo。综上所述，这些结果提高了我们对PRDM1在肢体基因调控网络中的作用的理解，并确定了与人类SHFM相关的新的PRDM1变体。斑马鱼Prdm1a富含脯氨酸/丝氨酸和锌指结构域是调控鳍诱导、生长和前后方模式形成所必需的。人类PRDM1变异体包含这些区域的中断，会导致手/脚分裂畸形。
Split hand/foot malformation (SHFM) is a rare limb abnormality with clefting of the fingers and/or toes. For many individuals, the genetic etiology is unknown. Through whole-exome and targeted sequencing, we detected three novel variants in a gene encoding a transcription factor, PRDM1, that arose de novo in families with SHFM or segregated with the phenotype. PRDM1 is required for limb development; however, its role is not well understood and it is unclear how the PRDM1 variants affect protein function. Using transient and stable overexpression rescue experiments in zebrafish, we show that the variants disrupt the proline/serine-rich and DNA-binding zinc finger domains, resulting in a dominant-negative effect. Through gene expression assays, RNA sequencing, and CUT&RUN in isolated pectoral fin cells, we demonstrate that Prdm1a directly binds to and regulates genes required for fin induction, outgrowth and anterior/posterior patterning, such as fgfr1a, dlx5a, dlx6a and smo. Taken together, these results improve our understanding of the role of PRDM1 in the limb gene regulatory network and identified novel PRDM1 variants that link to SHFM in humans. Zebrafish Prdm1a proline/serine-rich and zinc finger domains are required to regulate fin induction, outgrowth and anterior/posterior patterning. Human PRDM1 variants containing disruptions in these domains cause split hand/foot malformation.
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影响因子：
14.9
作者：
Gene Ontology Consortium
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Gene Ontology Consortium
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