Disease relevance of HSF4

• Locus heterogeneity in autosomal recessive congenital cataracts: linkage to 9q and germline HSF4 mutations [1].

High impact information on HSF4

• We screened individuals of three Chinese families for mutations in HSF4 (a gene at this locus that encodes heat-shock transcription factor 4) and discovered that in each family, a distinct missense mutation, predicted to affect the DNA-binding domain of the protein, segregates with the disorder [2].
• HSF4 is required for normal cell growth and differentiation during mouse lens development [3].
• In humans, missense mutation in the hsf4 gene causes cataract, and mice bearing a targeted disruption of the hsf4 gene exhibit defects in lens fiber cell differentiation and early cataract formation [4].
• Transient transfection of hHSF4 in HeLa cells, which do not express hHSF4, results in a constitutively active DNA binding trimer which, unlike other members of the HSF family, lacks the properties of a transcriptional activator [5].
• This stage-specific inverse relationship between the expression of HSF1/2 and HSF4 suggests tissue-specific management of stress depending on the presence or absence of specific HSF(s) [6].

Biological context of HSF4

• Here, we have determined the exon structure of the human HSF4 gene and identified a major new isoform, HSF4b, derived by alternative RNA splicing events, in addition to a previously reported HSF4a isoform [7].
• These results suggest that differential splicing of HSF4 mRNA gives rise to both an inhibitor and activator of tissue-specific heat shock gene expression [7].
• All exons and the splice sites of the HSF4 gene were sequenced in all members of the Tunisian family and in control individuals [8].
• Furthermore, novel CCAAT/enhancer binding protein beta (C/EBPbeta) and heat shock factor 4 (HSF4) transcription binding sites were identified on the rat mrp3 promoter [9].
• RESULTS: The cataract gene in the Chinese family was linked to marker D16S3043, and further haplotype analysis defined the causative gene between D16S515 and D16S415 within which HSF4 is located [10].

Anatomical context of HSF4

• While HSF1-3 had no significant effect on motility and viability of spermatozoa, HSF4 almost completely affected their survival [11].
• Normal human foreskin fibroblasts (HSF4) were transfected using the pSV3-neo plasmid [12].

Associations of HSF4 with chemical compounds

• A novel mutation c.221G>A was identified in HSF4, which results in substitution of a highly conserved arginine residue by histidine at codon 74 (p.R74H) [10].

Regulatory relationships of HSF4

• In summary, KLF6 and HSF4 are stimuli-specific regulatory elements which may be important in the control of the rat mdr1b and mrp3 genes during health and disease [9].
• KLF6 and HSF4 transcriptionally regulate multidrug resistance transporters during inflammation [9].

Other interactions of HSF4

• Endotoxin treatment significantly affected transcriptional activity only in C/EBPbeta and HSF4 double deletion mrp3 promoter constructs [9].
• Polymerase chain reaction/restriction fragment length polymorphism analysis was used to demonstrate cosegregation of the HSF4 mutation with the cataract and the absence of the mutation in the normal controls [10].

Analytical, diagnostic and therapeutic context of HSF4

• RT-PCR was used to detect different transcripts of the HSF4 gene in the human lens [8].

References