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Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract

Abstract

Congenital cataracts cause 10–30% of all blindness in children, with one-third of cases estimated to have a genetic cause1. Lamellar cataract is the most common type of infantile cataract2. We carried out whole-genome linkage analysis of Chinese individuals with lamellar cataract, and found that the disorder is associated with inheritance of a 5.11-cM locus on chromosome 16. This locus coincides with one previously described for Marner cataract3. We screened individuals of three Chinese families for mutations in HSF4 (a gene at this locus that encodes heat-shock transcription factor 4) and discovered that in each family, a distinct missense mutation, predicted to affect the DNA-binding domain of the protein, segregates with the disorder. We also discovered an association between a missense mutation and Marner cataract in an extensive Danish family. We suggest that HSF4 is critical to lens development.

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Figure 1: Lens opacity and pedigree structure of the Chinese family I.
Figure 2: Expression and mutation analysis of HSF4.
Figure 3: Mutation positions and evolutionary conservation of HSF4.

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Acknowledgements

We are grateful to all of the individuals described here for their contribution to this study. We thank F. Francis and Z. Chen for critical reading of this manuscript, and C. Lopez-Otin and F. Hejtmancik for providing samples for mutation analysis. This work was supported by the National High Technology “863” Programs of China, the National Science Fund for Distinguished Young Scholars and Xenon Genetics.

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Correspondence to Xiangyin Kong.

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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 31, 276–278 (2002). https://doi.org/10.1038/ng921

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