A novel missense mutation in the HSF4 gene of giant pandas with senile congenital cataracts

Abstract

Cataracts are a common cause of visual impairment and blindness in mammals. They are usually associated with aging, but approximately one third of cases have a significant genetic component. Cataracts are increasingly prevalent among aging populations of captive giant pandas (Ailuropoda melanoleuca) and it is therefore important to identify genetic determinants that influence the likelihood of cataract development in order to distinguish between congenital and age-related disease. Here we screened for cataract-related genetic effects using a functional candidate gene approach combined with bioinformatics to identify the underlying genetic defect in a giant panda with congenital cataracts. We identified a missense mutation in exon 10 of the HSF4 gene encoding heat shock transcription factor 4. The mutation causes the amino acid substitution R377W in a highly conserved segment of the protein between the isoform-specific and downstream hydrophobic regions. Predictive modeling revealed that the substitution is likely to increase the hydrophobicity of the protein and disrupt interactions with spatially adjacent amino acid side chains. The mutation was not found in 13 unaffected unrelated animals but was found in an unrelated animal also diagnosed with senile congenital cataract. The novel missense mutation in the HSF4 gene therefore provides a potential new genetic determinant that could help to predict the risk of cataracts in giant pandas.

RNA-Seq analysis in giant pandas reveals the differential expression of multiple genes involved in cataract formation

“…Mutations in the HSF4 gene have been shown to cause cataracts in humans and other mammals [ 55 ], including the recent discovery of a novel HSF4 mutation in pandas [ 56 ]. HSF4 is a transcriptional repressor and we proposed that the novel mutation we discovered in this gene is likely to affect its interactions with upstream signaling components, thus disrupting the genetic control of lens functions.…”