Cataracts are a phenotypic feature of autosomal dominant hypocalcaemia with hypercalciuria (ADHH): lessons from the Nuf mouse model with an activating calcium sensing receptor (CaSR) mutation
Fadil Hannan1, Alan Curley1, Paul Christie1, Brian Harding1, M Andrew Nesbit1, Michael Cheeseman2, Anthony Bron3 & Rajesh Thakker1
Activating mutations of the calcium sensing receptor (CaSR) result in autosomal dominant hypocalcaemia with hypercalciuria (ADHH), in which patients may also suffer from polyuria, polydipsia, nephrocalcinosis, renal impairment, and ectopic calcification. A mouse model, Nuf, with an activating Leu723Gln CaSR mutation has been reported to develop the features of ADHH as well as cataracts that consist of dot nuclear opacities, which have not been described in ADHH patients. We have therefore investigated a family known to have hypocalcaemia that co-segregates with a CaSR abnormality (Cys129Tyr). The family had 3 affected members, a mother aged 42 years and her 2 sons aged 16 and 11 years. The study protocol had ethical committee approval. The Cys129Tyr CaSR abnormality was functionally characterized by transient transfection of wild-type and the mutant CaSR constructs into HEK293 cells and assessing the alterations of intracellular calcium in response to changes in extracellular calcium. This demonstrated that the mutant CaSR (Tyr129) had a significantly lower EC50 when compared to wild-type (Tyr129 mutant EC50=0.98 mM±0.26 (n=4) versus the wild-type Cys129 EC50=2.74 mM±0.29 (n=4), P<0.01), consistent with an activating mutation. Slit lamp eye examination revealed each ADHH patient to have multiple, bilateral dot and streak, cortical lens opacities in the absence of subcapsular cataracts or nuclear changes. These appearances differed from the subcapsular cataracts that are observed to occur secondary to hypocalcaemia of other causes. Interestingly, the CaSR is expressed in lens epithelial cells and its abnormal activation may stimulate calpain protease activity that could lead to denaturation of cytoskeletal proteins or, an alteration in ionic composition which leads to cataract formation. Thus, our findings indicate that evaluation for cataracts in ADHH patients is important and that these changes may be distinguished from those of hypoparathyroidism.