PUBLICATION
PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation
- Authors
- Truong, B.T., Shull, L.C., Lencer, E., Bend, E.G., Field, M., Blue, E.E., Bamshad, M.J., Skinner, C., Everman, D., Schwartz, C.E., Flanagan-Steet, H., Artinger, K.B.
- ID
- ZDB-PUB-230422-50
- Date
- 2023
- Source
- Disease models & mechanisms 16(4): (Journal)
- Registered Authors
- Artinger, Kristin Bruk, Flanagan-Steet, Heather
- Keywords
- Limb, PRDM1, Pectoral fin, Split hand/foot malformation, Zebrafish
- Datasets
- GEO:GSE217486
- MeSH Terms
-
- Animals
- DNA
- Limb Deformities, Congenital*/genetics
- Positive Regulatory Domain I-Binding Factor 1
- Transcription Factors/genetics
- Zebrafish*/genetics
- Zinc Fingers
- PubMed
- 37083955 Full text @ Dis. Model. Mech.
Citation
Truong, B.T., Shull, L.C., Lencer, E., Bend, E.G., Field, M., Blue, E.E., Bamshad, M.J., Skinner, C., Everman, D., Schwartz, C.E., Flanagan-Steet, H., Artinger, K.B. (2023) PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation. Disease models & mechanisms. 16(4):.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping