HGNC Approved Gene Symbol: HSF4
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:67,163,761-67,169,941 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | Cataract 5, multiple types | 116800 | Autosomal dominant | 3 |
Heat-shock transcription factors (HSFs) activate heat-shock response genes under conditions of heat or other stresses. Other members of the HSF family include HSF1 (140580) and HSF2 (140581). Using chicken HSF3 as a probe to screen a human HeLa cDNA library, Nakai et al. (1997) isolated an additional family member, termed HSF4 by the authors. Based on the low level of amino acid identity between chicken HSF3 and HSF4, Nakai et al. (1997) concluded that HSF4 is a novel member of the HSF family, rather than the human homolog of chicken HSF3. They reported that the HSF4 sequence encodes a 463-amino acid polypeptide. Northern blotting revealed that HSF4 is expressed as a 2.5-kb mRNA in the heart, skeletal muscle, and brain, and at much lower levels in some other tissues. Nakai et al. (1997) found that HSF4 bound specifically to the heat-shock response element but repressed, rather than activated, transcription.
Nakai et al. (1997) used fluorescence in situ hybridization to map the HSF4 gene to chromosome 16q21.
Bu et al. (2002) screened individuals of 3 Chinese families with cataract mapping to chromosome 16 (CTRCT5; 116800) for mutations in the HSF4 gene and discovered that in each family, a distinct missense mutation, predicted to affect the DNA-binding domain of the protein, segregated with the disorder (602438.0001; 602438.0003-602438.0004). They also discovered a missense mutation in HSF4 (602438.0002) in the extensive Danish family with Marner cataract. Thus it appears that HSF4 is critical to lens development.
Lens opacity 11 (Lop11) is an autosomal recessive mouse cataract mutation that arose spontaneously in the RIIIS/J strain. At 3 weeks of age, affected mice exhibit total cataracts with vacuoles. Talamas et al. (2006) mapped the Lop11 locus to mouse chromosome 8, and they identified an early transposable element in intron 9 of the Hsf4 gene. The insertion alters splicing and results in a truncated Hsf4 protein.
Mellersh et al. (2007) found that 20 of 22 Boston terriers affected by early-onset hereditary cataract, which develops within the first year of life, were homozygous for an insertion in exon 9 of the Hsf4 gene that resulted in a premature stop codon and truncated protein. No mutations in the canine Hsf4 gene were associated with late-onset hereditary cataract, which develops between 3 and 6 years of age.
In affected members of a large Chinese family with lamellar cataract (CTRCT5; 116800), Bu et al. (2002) identified a heterozygous 348T-C transition resulting in a leu115-to-pro (L115P) substitution in the DNA-binding domain of HSF4. The leucine residue specified by codon 115 is conserved among yeast, C. elegans, Drosophila, mouse, rat, and human and within the mostly conserved DNA-binding domains of the heat-shock factors. The autosomal dominant lamellar cataract in this family was described as a perinuclear-shaped lens opacity with a transparent embryonic nucleus. The earliest age of observed onset was 15 months.
In affected members of a large Danish family segregating cataract, originally reported by Marner (1949) and studied by Eiberg et al. (1988) with demonstration of linkage to haptoglobin on chromosome 16q (CTRCT5; 116800), Bu et al. (2002) identified a heterozygous 362C-T transition in exon 3 of the HSF4 gene. The mutation was expected to result in substitution of a highly conserved arg120 residue by cysteine (R120C). The cataract in this Danish family occurred through 9 generations and was characterized by zonular stellate lens opacity with an anterior polar opacity and early childhood onset.
In a sporadic case of infantile lamellar cataract (CTRCT5; 116800), Bu et al. (2002) identified a heterozygous C-to-A transversion in exon 1 of the HSF4 gene resulting in an ala20-to-asp (A20D) substitution in the DNA-binding region. This individual's parents did not have this mutation; thus, the mutation occurred de novo.
In a sporadic case of unilateral lamellar cataract (CTRCT5; 116800), Bu et al. (2002) found a heterozygous ile87-to-val (I87V) substitution in the highly conserved DNA-binding domain of HSF4. The 46-year-old father carried the same mutation and showed a mild cataract with cortical water clefts and lamellar separation.
Bu, L., Jin, Y., Shi, Y., Chu, R., Ban, A., Eiberg, H., Andres, L., Jiang, H., Zheng, G., Qian, M., Cui, B., Xia, Y., Liu, J., Hu, L., Zhao, G., Hayden, M. R., Kong, X. Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. Nature Genet. 31: 276-278, 2002. [PubMed: 12089525] [Full Text: https://doi.org/10.1038/ng921]
Eiberg, H., Marner, E., Rosenberg, T., Mohr, J. Marner's cataract (CAM) assigned to chromosome 16: linkage to haptoglobin. Clin. Genet. 34: 272-275, 1988. [PubMed: 3233780] [Full Text: https://doi.org/10.1111/j.1399-0004.1988.tb02875.x]
Marner, E. A family with eight generations of hereditary cataract. Acta Ophthal. 27: 537-551, 1949.
Mellersh, C. S., Graves, K. T., McLaughlin, B., Ennis, R. B., Pettitt, L., Vaudin, M., Barnett, K. C. Mutation in HSF4 associated with early but not late-onset hereditary cataract in the Boston Terrier. J. Hered. 98: 531-533, 2007. [PubMed: 17611257] [Full Text: https://doi.org/10.1093/jhered/esm043]
Nakai, A., Tanabe, M., Kawazoe, Y., Inazawa, J., Morimoto, R. I., Nagata, K. HSF4, a new member of the human heat shock factor family which lacks properties of a transcriptional activator. Molec. Cell. Biol. 17: 469-481, 1997. [PubMed: 8972228] [Full Text: https://doi.org/10.1128/MCB.17.1.469]
Talamas, E., Jackson, L., Koeberl, M., Jackson, T., McElwee, J. L., Hawes, N. L., Chang, B., Jablonski, M. M., Sidjanin, D. J. Early transposable element insertion in intron 9 of the Hsf4 gene results in autosomal recessive cataracts in lop11 and ldis1 mice. Genomics 88: 44-51, 2006. [PubMed: 16595169] [Full Text: https://doi.org/10.1016/j.ygeno.2006.02.012]