Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in Split Hand/Foot Malformation

ABSTRACT: Split Hand/Foot Malformation (SHFM) is a rare limb abnormality with clefting of the fingers and/or toes. For many patients, the genetic etiology is unknown. Through whole exome and targeted sequencing, we detected three novel variants in a transcription factor, PRDM1 that arose de novo in families with SHFM or segregated with the phenotype. PRDM1 has been shown to be 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 have reduced function compared to wildtype PRDM1 likely due to disruption of the proline/serine-rich and DNA-binding zinc finger domains. Through expression assays, RNA-seq, and CUT&RUN in isolated pectoral fin cells, we demonstrate that Prdm1a directly binds to and regulates genes required for limb induction, outgrowth, and anterior/posterior patterning, such as fgfr1a, dlx5a, dlx6a, and smo. Together, these results improve our understanding of the role of PRDM1 in the limb gene regulatory network and help predict the pathogenicity of PRDM1 variants in humans

ORGANISM(S): Danio rerio

PROVIDER: GSE217486 | GEO | 2023/04/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Nonsyndromic Split-Hand/Foot Malformation: Recent Classification.

Project description:Split-hand/foot malformation (SHFM) is a genetic limb anomaly disturbing the central rays of the autopod. SHFM is a genetically heterogeneous disorder with variable expressivity inherited as syndromic and nonsyndromic forms. We provide an update of the clinical and molecular aspects of nonsyndromic SHFM. This rare condition is highly complex due to the clinical variability and irregular genetic inheritance observed in the affected individuals. Nonsyndromic SHFM types have been reviewed in terms of major molecular genetic alterations reported to date. This updated overview will assist researchers, scientists, and clinicians in making an appropriate molecular diagnosis, providing an accurate recurrence risk assessment, and developing a management plan.

| S-EPMC6997797 | biostudies-literature

PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in Split Hand/Foot Malformation

Project description:PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in Split Hand/Foot Malformation

| PRJNA899096 | ENA

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [scRNA-seq]

Project description:Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigated the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice resulted in restructuring of the chromatin architecture. This led to an ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern. Artificial repositioning of the AER-specific enhancers of Fgf8 was sufficient to induce misexpression of Lbx1 and Btrc. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression and dosage in the developing limb. Our results reveal new insights into the molecular mechanism underlying SHFM3 and provide novel conceptual framework for how genomic rearrangements can cause gene misexpression and disease.

2023-02-22 | GSE223456 | GEO

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [RNA-seq]

2023-02-22 | GSE223455 | GEO

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [4C-seq]

2023-02-22 | GSE223454 | GEO

Genetic analysis of a congenital split?hand/split?foot malformation 4 pedigree.

Project description:In the present study whole-exome sequencing using the Complete Genomics platform was employed to scan a proband from a split?hand/split?foot malformation (SHFM) 4 family. The missense mutation c.728G>A (p.Arg243Gln) in the TP63 gene was revealed to be associated with SHFM. Sanger sequencing confirmed the sequences of the proband and his father. The father was diagnosed with SHFM and harbored a CGG?to?CAG mutation in exon 5, which produced a R243Q substitution in the zinc binding site and dimerization site of TP63. The R243Q mutation was predicted to be pathogenic by PolyPhen?2. The proband, who was diagnosed with four digit SHFM, exhibited a more severe phenotype. X?ray analysis returned the following results: Absence of third phalange bilaterally and third metacarpus of the left hand; absence of the second toes bilaterally and partial third toes; and partial fusion of the second, third and metatarsal bones of the right side with deformity of the second metatarsal of the right side. Osteochondroma was present in the fourth proximal radial metacarpal of the left hand and the basal and proximal parts of the second metatarsal of the right side. The proband's father had five digits in both feet. These results indicate that the R243Q mutation produces a novel phenotype named SHFM4. The present study revealed that the R243Q mutation in the TP63 gene produced a novel phenotype named SHFM4, thereby demonstrating the mutational overlap between ectrodactyly?ectodermal dysplasia?cleft syndrome and SHFM4.

| S-EPMC5983954 | biostudies-literature

Reconstruction of a Monodactylous Hand with Microsurgical Free Foot-to-Hand Transfer in Split-Hand/Split-Foot Malformation with Tibial Aplasia.

Project description:Split-hand/split-foot malformation with long bone deficiency (SHLFD syndrome) is a rare congenital disorder, which may be sporadic or autosomal dominant with incomplete penetrance. When complete tibial aplasia is seen, the mainstay of treatment is amputation and lower limb prosthesis. This rare constellation of congenital differences presents an opportunity for microsurgical free tissue transfer using the principle of "spare parts" to improve the functionality of the hand. We present a rare case of split-hand/split-foot malformation with a monodactylous right hand and complete tibial aplasia, treated with microsurgical free foot-to-hand transfer at the time of lower limb amputation, reconstructing key pinch. At the latest 8 months follow-up, the patient had no pain, active key pinch, and ambulated independently with prostheses. He was able to use his right hand independently for a number of daily activities, such as stacking blocks, drinking from a cup, and playing with toys.

| S-EPMC7159962 | biostudies-literature

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3 [Capture Hi-C, Virtual4C]

2023-02-22 | GSE223450 | GEO

Evidence for locus heterogeneity in human autosomal dominant split hand/split foot malformation.

Project description:Split hand/split foot (SHSF; also known as ectrodactyly) is a human developmental disorder characterized by missing central digits and other distal limb malformations. An association between SHSF and cytogenetically visible rearrangements of chromosome 7 at bands q21-q22 provides compelling evidence for the location of a causative gene at this location, and the locus has been designated SHFD1. In the present study, marker loci were localized to the SHFD1 critical region through the analysis of somatic cell hybrids derived from individuals with SHSF and cytogenetic abnormalities involving the 7q21-q22 region. Combined genetic and physical data suggest that the order of markers in the SHFD1 critical region is cen-D7S492-D7S527-(D7S479-D7S491)-SHFD1-++ +D7S554-D7S518-qter. Dinucleotide repeat polymorphisms at three of these loci were used to test for linkage of SHSF to this region in a large pedigree that demonstrates autosomal dominant SHSF. Evidence against linkage of the SHSF gene to 7q21-q22 was obtained in this pedigree. Therefore, combined molecular and genetic data provide evidence for locus heterogeneity in autosomal dominant SHSF. We propose the name SHSF2 for this second locus.

| S-EPMC1918225 | biostudies-other

Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.

Project description:Split-hand/split-foot malformation (SHFM), a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals, is phenotypically analogous to the naturally occurring murine Dactylaplasia mutant (Dac). Results of recent studies have shown that, in heterozygous Dac embryos, the central segment of the apical ectodermal ridge (AER) degenerates, leaving the anterior and posterior segments intact; this finding suggests that localized failure of ridge maintenance activity is the fundamental developmental defect in Dac and, by inference, in SHFM. Results of gene-targeting studies have demonstrated that p63, a homologue of the cell-cycle regulator TP53, plays a critically important role in regulation of the formation and differentiation of the AER. Two missense mutations, 724A-->G, which predicts amino acid substitution K194E, and 982T-->C, which predicts amino acid substitution R280C, were identified in exons 5 and 7, respectively, of the p63 gene in two families with SHFM. Two additional mutations (279R-->H and 304R-->Q) were identified in families with EEC (ectrodactyly, ectodermal dysplasia, and facial cleft) syndrome. All four mutations are found in exons that fall within the DNA-binding domain of p63. The two amino acids mutated in the families with SHFM appear to be primarily involved in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with the DNA.

| S-EPMC1287102 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data