PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand/foot malformation.
Dis Model Mech
; 16(4)2023 04 01.
Article
in En
| MEDLINE
| ID: mdl-37083955
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Zebrafish
/
Limb Deformities, Congenital
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Dis Model Mech
Journal subject:
MEDICINA
Year:
2023
Type:
Article
Affiliation country:
United States