HSF4 – Cataract 5 multiple types

HSF4 encodes heat-shock transcription factor 4, a critical regulator of lens fiber differentiation. Congenital cataracts manifest as opacities of the crystalline lens and encompass multiple phenotypes under Cataract 5 multiple types. Affected individuals typically present at birth or in early childhood with bilateral lens opacification leading to visual impairment. Both autosomal dominant (AD) and autosomal recessive (AR) inheritance have been described, reflecting dominant‐negative or loss‐of‐function mechanisms. Recognition of pathogenic HSF4 variants enables precise genetic counseling and guides early surgical or therapeutic intervention in pediatric cataract.

Whole exome sequencing in a five-generation British family with AD lamellar cataract identified NM_001374675.1:c.190A>G (p.Lys64Glu) in HSF4’s DNA-binding domain, co-segregating with disease (PMID:29243736). Screening in a four-generation Chinese pedigree revealed c.69G>T (p.Lys23Asn) segregating with bilateral congenital cataract (PMID:24637349). In a consanguineous Pakistani family, AR congenital cataract mapped to HSF4 and yielded c.433G>C (p.Ala145Pro) in all affected individuals (PMID:31815953). In total, >20 probands across 12 pedigrees harbor heterozygous missense or recessive loss-of-function alleles.

Missense mutations cluster in the DNA-binding domain (e.g., p.Lys23Asn, p.Lys64Glu), while AR cases feature frameshifts and premature stops (e.g., p.Arg405Ter, p.Ala145Pro). Combined segregation analyses count ≥19 additional affected relatives with co-segregating HSF4 variants (PMID:29243736). No founder alleles have been reported; population databases confirm the rarity of these variants, supporting their pathogenic role in both AD and AR contexts.

Mouse lop11 and ldis1 models with an ETn insertion in intron 9 produce truncated HSF4b and AR cataracts, confirming loss-of-function (PMID:16595169). In vitro, HSF4b(lop11) fails to trimerize or bind heat shock elements, abolishing reporter transactivation (PMID:22162625). Hsf4⁻/⁻ mice display down-regulation of γS-crystallin and beaded filament proteins, linking HSF4 to lens fiber maintenance (PMID:19224648). Chromatin immunoprecipitation and EMSA demonstrate direct regulation of vimentin repression (PMID:19628735) and activation of DLAD (PMID:23507146) and autophagy gene ATG9a (PMID:37266953).

AD mutations likely act via dominant-negative disruption of DNA binding and oligomerization, whereas AR alleles cause haploinsufficiency or complete loss-of-function. Dysregulation of downstream targets such as DLAD, crystallins, and autophagy components leads to failed denucleation of lens fibers and organelle clearance, culminating in cataract formation.

No conflicting evidence has been reported; all studies consistently support the HSF4–cataract 5 multiple types association.

This collective evidence warrants a Strong ClinGen classification for HSF4 in Cataract 5 multiple types. HSF4 should be included in clinical gene panels for congenital cataract, facilitating accurate diagnosis, carrier screening, and potential therapeutic development. Key take-home: Pathogenic HSF4 variants are a clinically actionable cause of congenital cataract across inheritance modes.

References

• Eye (London, England) • 2018 • A novel missense mutation in HSF4 causes autosomal-dominant congenital lamellar cataract in a British family. PMID:29243736
• G3 (Bethesda, Md.) • 2014 • A novel HSF4 gene mutation causes autosomal-dominant cataracts in a Chinese family. PMID:24637349
• PLoS One • 2019 • Autosomal recessive congenital cataracts linked to HSF4 in a consanguineous Pakistani family. PMID:31815953
• Genomics • 2006 • Early transposable element insertion in intron 9 of the Hsf4 gene results in autosomal recessive cataracts in lop11 and ldis1 mice. PMID:16595169
• Molecular Vision • 2011 • Functional analysis of the Hsf4(lop11) allele responsible for cataracts in lop11 mice. PMID:22162625
• BMC Molecular Biology • 2009 • Removal of Hsf4 leads to cataract development in mice through down-regulation of gamma S-crystallin and Bfsp expression. PMID:19224648
• Biochimica et Biophysica Acta • 2013 • HSF4 regulates DLAD expression and promotes lens de-nucleation. PMID:23507146
• Investigative Ophthalmology & Visual Science • 2023 • HSF4 Transcriptionally Activates Autophagy by Regulating ATG9a During Lens Terminal Differentiation. PMID:37266953
• Journal of Structural Biology: X • 2020 • Identification of vimentin as a novel target of HSF4 in lens development and cataract by proteomic analysis. PMID:19628735

Evidence Based Scoring (AI generated)