Functional impairment of lens aquaporin in two families with dominantly inherited cataracts

Opacities in the crystalline lens of eye appear with high frequency in the general population. Dominantly inherited cataracts with differing clinical features were found in two families carrying different point mutations in t he gene encoding lens water channel protein AQPO (major intrinsic protein, MIP), Families with E134G have a uni-lamellar cataract which is stable afte r birth, whereas families with T138R have multi-focal opacities which incre ase throughout life. To establish pathophysiological relevance of cataract formation, the Xenopus laevis oocyte expression system was employed to eval uate functional defects in the mutant proteins, E134G and T138R. Both subst itutions cause loss of membrane water channel activity due to impaired traf ficking of the mutant proteins to the oocyte plasma membrane. Although miss ense mutations in AQP1 and AQP2 proteins are known to result in recessive t raits in vivo and in vitro, when E134G or T138R are co-expressed with wild- type AQPO protein, the mutant proteins exhibit dominant negative behaviour. To our knowledge, these studies represent the first in vitro demonstration of functionally defective AQPO protein from humans with congenital catarac ts. Moreover, these observations predict that less severe defects in the AQ PO protein may contribute to lens opacity in patients with common, less ful minant forms of cataracts.