Human Molecular Genetics, 2000, Vol. 9, No. 15 2329-2334
© 2000 Oxford University Press
Functional impairment of lens aquaporin in two families with dominantly inherited cataracts
1Department of Molecular Genetics, Institute of Ophthalmology, University College and Moorfields Eye Hospital, 11–43 Bath Street, London EC1V 9EL, UK, 2Department of Biological Chemistry, Johns Hopkins University School of Medicine, 75 North Wolfe Street, Baltimore, MD 21205-2185, USA, 3Addenbrookes Hospital, Cambridge, UK and 4National Eye Institute, National Institutes of Health, Bethesda, MD, USA
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 the gene encoding lens water channel protein AQP0 (major intrinsic protein, MIP). Families with E134G have a uni-lamellar cataract which is stable after birth, whereas families with T138R have multi-focal opacities which increase throughout life. To establish pathophysiological relevance of cataract formation, the Xenopus laevis oocyte expression system was employed to evaluate functional defects in the mutant proteins, E134G and T138R. Both substitutions cause loss of membrane water channel activity due to impaired trafficking of the mutant proteins to the oocyte plasma membrane. Although missense mutations in AQP1 and AQP2 proteins are known to result in recessive traits in vivo and in vitro, when E134G or T138R are co-expressed with wild-type AQP0 protein, the mutant proteins exhibit dominant negative behaviour. To our knowledge, these studies represent the first in vitro demonstration of functionally defective AQP0 protein from humans with congenital cataracts. Moreover, these observations predict that less severe defects in the AQP0 protein may contribute to lens opacity in patients with common, less fulminant forms of cataracts.
+ These authors contributed equally to this work
§ To whom correspondence should be addressed. Tel: +1 410 955 7049; Fax: +1 410 955 3149; Email: pagre@jhmi.edu
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