Dataset Information

Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects.

ABSTRACT: Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at https://www.LOVD.nl/FOXE3, https://www.LOVD.nl/HSF4, https://www.LOVD.nl/MAF, and https://www.LOVD.nl/PITX3. Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases.

SUBMITTER: Anand D

PROVIDER: S-EPMC5839989 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects.

Anand Deepti D Agrawal Smriti A SA Slavotinek Anne A Lachke Salil A SA

Human mutation 20180116 4

Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are ...[more]

PMID: 29314435

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Project description:BackgroundCongenital cataract, a kind of cataract presenting at birth or during early childhood, is a leading cause of childhood blindness. To date, more than 30 genes on different chromosomes are known to cause this disorder. This study aimed to identify the HSF4 mutations in a cohort from Chinese families affected with congenital cataracts.MethodsForty-two unrelated non-syndromic congenital cataract families and 112 ethnically matched controls from southeast China were recruited from the southeast of China. We employed Sanger sequencing method to discover the variants. To confirm the novel mutations, STR haplotypes were constructed to check the co-segregation with congenital cataract. The pathogenic potential of the novel mutations were assessed using bioinformatics tools including SIFT, Polyphen2, and Human Splicing Finder. The pathogenicity of all the mutations was evaluated by the guidelines of American College of Medical Genetics and InterVar software.ResultsNo previously reported HSF4 mutations were found in all the congenital cataract families. Five novel HSF4 mutations including c.187 T > C (p.Phe63Leu), c.218G > T (p.Arg73Leu), c.233A > G (p.Tyr78Cys), IVS5 c.233-1G > A and c.314G > C (p.Ser105Thr) were identified in five unrelated families with congenital cataracts, respectively. These mutations co-segregated with all affected individuals in each family were not observed in the unaffected family members or in 112 unrelated controls. All five mutations were categorized to be the disease "pathogenic" according to ACMG guidelines and using InterVar software. Mutations in the HSF4 were responsible for 11.90% Chinese families with congenital cataracts in our cohort.ConclusionsIn the study, we identified five novel HSF4 mutations in Chinese families with congenital cataracts. Our results expand the spectrum of HSF4 mutations causing congenital cataracts, which may be helpful for the molecular diagnosis of congenital cataracts in the era of precision medicine.

Project description:Lens opacity 11 (lop11) is a spontaneous autosomal recessive mouse mutation resulting in cataracts. Insertion of an early transposable element (ETn) in intron 9 of heat shock factor 4 (Hsf4) was previously identified as responsible for lop11 cataracts. Although molecular analysis showed that the ETn insertion resulted in an aberrant Hsf4 transcript encoding a truncated mutant HSF4(lop11) protein, the function of the mutant HSF4(lop11) protein was not investigated. The goal of this study was to functionally evaluate the mutant HSF4(lop11) protein and to establish the onset and progression of cataracts in lop11 lenses.HSF4 is expressed as two alternatively transcribed isoforms Hsf4a and Hsf4b. Given that only Hsf4b is expressed in the lens we pursued evaluation of the mutant Hsf4b isoform only. Recombinant wild type HSF4b and mutant HSF4b(lop11) proteins were analyzed using elecrophoretic mobility shift, reporter transactivation, western blotting and protein half-life assays in HEK293 cells. Prenatal and postnatal wild type and lop11 lenses were evaluated using a combination of clinical, histological, and immunohistological analyses.HSF4b(lop11) stability and nuclear translocation of did not differ from wild type HSF4b. However, HSF4b(lop11) exhibited abolished HSE-mediated DNA binding and transactivation. Further investigation identified that HSF4b(lop11) fails to form trimers. Histological analysis of lop11 lenses indicated the persistence of nuclei in lens fiber cells as early as postnatal day 0.5 (P0.5). No differences were observed between wild type and lop11 in lens epithelial cell proliferation and spatio-temporal differentiation to fiber cells. However, by P10-12, lop11 lenses develop severely vacuolated cataracts commonly accompanied by rupture of the lens capsule and release of the lenticular material in the vitreous cavity. Clinically, lop11 vacuolated cataracts were visible upon eyelid opening between P12-14.The ETn insertion in lop11 mice results in abolished HSF4b function. Loss of 132 amino acids from the COOH-terminus in HSF4b(lop11) results in the failure of trimer formation and subsequent failure of HSE-mediated DNA binding and transactivation. These findings highlight the importance of the COOH-terminal region for normal function. The persistence of nuclei in postnatal lop11 lens fiber cells was identified as the initial lens abnormality, thus confirming a previously identified role of HSF4b in denucleation of lens fiber cells. By P14 lop11 lenses develop severe fiber cell vacuoles although how the loss of HSF4b function results in this process remains unknown. Collectively, these findings further our understanding of the mechanism of HSF4 loss of function as well as the resulting implications on lop11 cataractogenesis.

Dataset Information

Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects.

Publications

Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects.

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