A novel missense mutation in the gene encoding major intrinsic protein (MIP) in a Giant panda with unilateral cataract formation

Abstract

Background Cataracts are defects of the lens that cause progressive visual impairment and ultimately blindness in many vertebrate species. Most cataracts are age-related, but up to one third have an underlying genetic cause. Cataracts are common in captive zoo animals, but it is often unclear whether these are congenital or acquired (age-related) lesions. Results Here we used a functional candidate gene screening approach to identify mutations associated with cataracts in a captive giant panda (Ailuropoda melanoleuca). We screened 11 genes often associated with human cataracts and identified a novel missense mutation (c.686G > A) in the MIP gene encoding major intrinsic protein. This is expressed in the lens and normally accumulates in the plasma membrane of lens fiber cells, where it plays an important role in fluid transport and cell adhesion. The mutation causes the replacement of serine with asparagine (p.S229N) in the C-terminal tail of the protein, and modeling predicts that the mutation induces conformational changes that may interfere with lens permeability and cell–cell interactions. Conclusion The c.686G > A mutation was found in a captive giant panda with a unilateral cataract but not in 18 controls from diverse regions in China, suggesting it is most likely a genuine disease-associated mutation rather than a single-nucleotide polymorphism. The mutation could therefore serve as a new genetic marker to predict the risk of congenital cataracts in captive giant pandas.

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

“…For example, mutations in the major intrinsic protein (MIP, also known as aquaporin 0) promote cataract formation in human infants, and several strains of rats and mice with loss-of-function mip mutations also develop fully penetrant cataracts [ 31 – 35 ]. More recently, we reported a novel mutation in the panda Mip gene also associated with cataract formation [ 36 ]. Transcriptomic analysis in juvenile mip −/− knockout mice identified 29 genes with > 2-fold changes in expression, including the mitochondrial translocase ( Timmdc1 ), a matrix metallopeptidase ( Mmp2 ), a Rho GTPase-interacting protein ( Ubxn11 ) and a transcription factor ( Twist2 ) which were strongly upregulated, and a proteasome subunit ( Psmd8 ), a ribonuclease ( Pop4 ), and a heat-shock protein ( Hspb1 ) that were strongly downregulated [ 37 ].…”

“…Routine physical examinations were carried out every month on the living captive animals, including eye, mouth and nose and general physical appearance, abdominal palpation, and general clinical signs. Blood was collected once a month for the analysis of physiological and biochemical indicators in order to exclude risk factors such as injury, diabetes or other diseases that can promote cataract formation [ 36 ].…”