Human Molecular Genetics, 2000, Vol. 9, No. 20 3011-3018
© 2000 Oxford University Press
Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1
1Telethon Institute of Genetics and Medicine (TIGEM), 20132 Milan, Italy, 2Department of Experimental Medicine, Anatomy Section, University of Genoa, 16132 Genoa, Italy, 3Medical Genetics, Department of Pediatrics, University of Padua, 35128 Padua, Italy, 4IDI IRCCS, Istituto Dermopatico dell’Immacolata, 00167 Rome, Italy and 5Università Vita-Salute San Raffaele, 20132 Milan, Italy
Ocular albinism type 1 (OA1) is an X-linked disorder mainly characterized by a severe reduction of visual acuity, hypopigmentation of the retina and the presence of macromelanosomes in the skin and eyes. Various types of mutation have been identified within the OA1 gene in patients with the disorder, including several missense mutations of unknown functional significance. In order to shed light into the molecular pathogenesis of ocular albinism and possibly define critical functional domains within the OA1 protein, we characterized 19 independent missense mutations with respect to processing and subcellular distribution on expression in COS-7 cells. Our analysis indicates the presence of at least two distinct biochemical defects associated with the different missense mutations. Eleven of the nineteen OA1 mutants (
60%) were retained in the endoplasmic reticulum, showing defecNStive intracellular transport and glycosylation, consistent with protein misfolding. The remaining eight of the nineteen OA1 mutants (40%) displayed sorting and processing behaviours indistinguishable from those of the wild-type protein. Consistent with our recent findings that OA1 represents a novel type of intracellular G protein-coupled receptor (GPCR), we found that most of these latter mutations cluster within the second and third cytosolic loops, two regions that in canonical GPCRs are known to be critical for their downstream signaling, including G protein-coupling and effector activation. The biochemical analysis of OA1 mutations performed in this study provides important insights into the structure–function relationships of the OA1 protein and implies protein misfolding as a major pathogenic mechanism in OA1.
+ These authors contributed equally to this work
§ Present address: TIGEM, Via Pietro Castellino 111, 80131 Naples, Italy
¶ Present address:DIBIT, Scientific Institute San Raffaele, Via Olgettina 58, 20132 Milano, Italy
To whom correspondence should be addressed. Tel: +39 022 1560 233; Fax: +39 022 1560 220; Email: schiaffi@tigem.it
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