HSF4 gene


Gene (OMIM No.)
Function of gene/protein
  • Protein: Heat-shock transcription factor 4
  • Regulates gene transcription during lens development (transcription factor)
  • Protects lens protein from stressors and regulates differentiation of lens fibre cells
  • Expressed ubiquitously at low levels but enhanced in heart, skeletal muscle, brain and lung cells
Clinical phenotype
(OMIM phenotype no.)
  • Cataract 5, multiple types (#116800)
  • Multiple types: lamellar, zonular stellate, anterior polar cataract
  • Autosomal recessive
  • Autosomal dominant
Ocular features
Systemic features
  • No extraocular features have been reported
Key investigations
  • B-scan USS to measure axial length to document microphthalmia and detect any posterior segment abnormalities
  • Electrophysiology
  • TORCH screen
  • Assessment with a pediatrician if suspicious of systemic involvement
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (cataract)
  • Whole exome sequencing
  • Whole genome sequencing
Therapies under research
  • None at present
Further information

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Additional information

Pathogenic missense variants in the HSF4 protein’s DNA-binding domain are inherited in an AD manner while bialleic variants (AR) in other functional domains are required to cause a clinical phenotype. Based on this observation, Anand et al suggests that the DNA-binding domain is integral to HSF4 function.[4]

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  1.  Bu L, Jin Y, Shi Y, et al. Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. Nat Genet. 2002;31(3):276‐278
  2.  Mellersh CS, Graves KT, McLaughlin B, et al. Mutation in HSF4 associated with early but not late-onset hereditary cataract in the Boston Terrier. J Hered. 2007;98(5):531‐533
  3.  Berry V, Pontikos N, Moore A, et al. A novel missense mutation in HSF4 causes autosomal-dominant congenital lamellar cataract in a British family. Eye (Lond). 2018;32(4):806-812
  4.  Anand D, Agrawal SA, Slavotinek A, Lachke SA. Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects. Hum Mutat. 2018;39(4):471-494
  5.  Talamas E, Jackson L, Koeberl M, et al. Early transposable element insertion in intron 9 of the Hsf4 gene results in autosomal recessive cataracts in lop11 and ldis1 mice. Genomics. 2006;88(1):44‐51
  6.  Fujimoto M, Izu H, Seki K, et al. HSF4 is required for normal cell growth and differentiation during mouse lens development. EMBO J. 2004;23(21):4297-4306
  7.  Gao M, Huang Y, Wang L, et al. HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators. Cell Death Dis. 2017;8(10):e3082

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Updated on November 30, 2020
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