A Novel HSF4 Gene Mutation Causes Autosomal-Dominant Cataracts in a Chinese Family

Abstract

Congenital cataracts are a significant cause of visual impairment or blindness in children. One-third of cases estimated to have a genetic cause. We carried out gene analysis and bioinformatics analysis to map the locus and to identify the underlying genetic defect in a 12-member, four-generation Chinese family affected with bilateral congenital cataracts. We screened individuals of the family and discovered a distinct missense mutation in HSF4 (a gene at this locus that encodes teat-shock transcription factor 4). Bioinformatics analysis was used to determine possible changes in the protein structure that could affect the phenotype. Sequencing of the candidate genes showed a heterozygous c.69 G→T change in the heat shock transcription factor 4 (HSF4) gene, which resulted in the substitution of a lysine with an asparagine (p. K23N). This mutation cosegregated with all affected individuals and was not observed in unaffected family members. Bioinformatics analysis indicated that the p. K23N mutation was predicted to be disease causing. This is the first report of the novel missense mutation, c.69 G→T (p. K23N), in exon 3 of the HSF4 locus on 16q21-q22 associated with bilateral congenital cataracts in a Chinese family. This novel mutation could enable propergenetic diagnostics and counseling in affected families and could lead to a better understanding of the structure and function of HSF4 in health and disease.

Molecular Mechanisms of Heat Shock Factors in Cancer

“…In primary human lens epithelial cells, HSF4 has been shown to directly bind to and stabilize p53, subsequently resulting in cell cycle arrest and reduced proliferation [73]. Furthermore, the importance of HSF4 in human lens development is highlighted by reports showing that a number of mutations in the DNA-binding domain of HSF4 are related to severe cases of chromosomal dominant hereditary cataract [74][75][76]. HSF4 is also involved in olfactory neurogenesis by modulating the expression of leukemia inhibitory factor (LIF), a key cytokine involved in normal development of olfactory sensory neurons [56,77].…”

Missense mutation of a class B heat shock factor is responsible for the tomato bushy root-2 phenotype

“…The S75C brt-2 mutation is located in the conserved Hsf DBD domain and a blast search revealed that S75 in the sequence context SFVRQ is absolutely conserved across all eukaryotic organisms and in all members of the Hsf family (Lv et al, 2014 ). A crystal structure for human Hsf1 shows that the equivalent of S75 (S68 in human Hsf1) occurs within the α3 helix that contacts the major groove of the DNA within the specific nucleotide sequence of the heat shock element (HSE), forming a hydrogen bond with the DNA phosphate backbone (Neudegger et al, 2016 ).…”

Screening of potential target genes for cataract by analyzing mRNA expression profile of mouse Hsf4-null lens

“…Cataractogenesis has multiple causes and is often associated with an abnormality of the lens microarchitecture [ 31 ]. Hsf4 is prominently expressed in the lens compared with in other tissues and closely related to the development of cataract [ 5 , 32 ]. In the present study, we aimed to extend our understanding of the influence of lens development caused by Hsf4 mutations.…”