PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation

Dis Model Mech. 2023 Apr 1;16(4):dmm049977. doi: 10.1242/dmm.049977. Epub 2023 Apr 21.


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.

Keywords: Limb; PRDM1; Pectoral fin; Split hand/foot malformation; Zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA
  • Limb Deformities, Congenital* / genetics
  • Positive Regulatory Domain I-Binding Factor 1
  • Transcription Factors / genetics
  • Zebrafish* / genetics
  • Zinc Fingers


  • DNA
  • Positive Regulatory Domain I-Binding Factor 1
  • Transcription Factors
  • prdm1a protein, zebrafish

Supplementary concepts

  • Ectrodactyly
  • Split hand foot deformity