A Common Temperature-sensitive Allelic Form of Human Tyrosinase Is Retained in the Endoplasmic Reticulum at the Nonpermissive Temperature

Oculocutaneous albinism type 1TS is caused by mutations that render the melanocyte-specific enzyme tyrosinase temperature-sensitive (ts); the enzyme is inactive in cells grown at 37 °C but displays full activity in cells grown at 31 °C. To distinguish whether the ts phenotype of the common R402Q variant of human tyrosinase is due to altered enzymatic activity or to misfolding and a defect in intracellular trafficking, we analyzed its localization and processing in transiently transfected HeLa cells. R402Q tyrosinase accumulates in the endoplasmic reticulum (ER) at 37 °C but exits the ER and accumulates in endosomal structures in cells grown at 31 °C. The inability of the R402Q variant to exit the ER is confirmed by the failure to acquire endoglycosidase H resistance at 37 °C and cannot be accounted for solely by enhanced proteasome-mediated degradation. ER retention at 37 °C is mediated by the lumenal domain of R402Q tyrosinase, is not dependent on tethering to the membrane, and is irreversible. Finally, a wild-type allelic form of tyrosinase is partially ts in transiently transfected HeLa cells. The data show that human tyrosinase expressed in non-melanogenic cells folds and exits the ER inefficiently and that R402Q tyrosinase exaggerates this defect, resulting in a failure to exit the ER at physiologic temperatures. Oculocutaneous albinism type 1TS is caused by mutations that render the melanocyte-specific enzyme tyrosinase temperature-sensitive (ts); the enzyme is inactive in cells grown at 37 °C but displays full activity in cells grown at 31 °C. To distinguish whether the ts phenotype of the common R402Q variant of human tyrosinase is due to altered enzymatic activity or to misfolding and a defect in intracellular trafficking, we analyzed its localization and processing in transiently transfected HeLa cells. R402Q tyrosinase accumulates in the endoplasmic reticulum (ER) at 37 °C but exits the ER and accumulates in endosomal structures in cells grown at 31 °C. The inability of the R402Q variant to exit the ER is confirmed by the failure to acquire endoglycosidase H resistance at 37 °C and cannot be accounted for solely by enhanced proteasome-mediated degradation. ER retention at 37 °C is mediated by the lumenal domain of R402Q tyrosinase, is not dependent on tethering to the membrane, and is irreversible. Finally, a wild-type allelic form of tyrosinase is partially ts in transiently transfected HeLa cells. The data show that human tyrosinase expressed in non-melanogenic cells folds and exits the ER inefficiently and that R402Q tyrosinase exaggerates this defect, resulting in a failure to exit the ER at physiologic temperatures. oculocutaneous albinism type 1 cycloheximide proteinN-glycanase F endoglycosidase H endoplasmic reticulum immunofluorescence microscopy methionine methyl ester wild-type temperature-sensitive hemagglutinin phosphate-buffered saline polyacrylamide gel electrophoresis Oculocutaneous albinism type 1 (OCA1)1comprises a group of human disorders characterized by reduced or absent skin pigmentation, vision defects due to reduced optical pigmentation and to misrouting of optic nerve fibers, and enhanced sensitivity to skin and optical cancers (1.King R.A. Hearing V.J. Creel D.J. Oetting W.S. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. III. McGraw-Hill Inc., New York1995: 4353-4392Google Scholar). These disorders are caused by germline mutations within the coding region of the melanocyte-specific gene product tyrosinase (2.Giebel L.B. Tripathi R.K. Strunk K.M. Hanifin J.M. Jackson C.E. King R.A. Spritz R.A. Am. J. Hum. Genet. 1991; 48: 1159-1167PubMed Google Scholar, 3.Tripathi R.K. Strunk K.M. Giebel L.B. Weleber R.G. Spritz R.A. Am. J. Med. Genet. 1992; 43: 865-871Crossref PubMed Scopus (56) Google Scholar, 4.Tomita Y. J. Invest. Dermatol. 1993; 100 (suppl.): 186-190Abstract Full Text PDF Scopus (21) Google Scholar). Tyrosinase, a key enzyme in the synthesis of melanin (reviewed in Ref. 5.del Marmol V. Beermann F. FEBS Lett. 1996; 381: 165-168Crossref PubMed Scopus (350) Google Scholar) is a type I integral membrane glycoprotein that is specifically expressed in cells of the melanocyte lineage, where it localizes to a specialized late endosome-like compartment, the melanosome (6.Orlow S.J. J. Invest. Dermatol. 1995; 105: 3-7Abstract Full Text PDF PubMed Scopus (235) Google Scholar). Within melanosomes, tyrosinase initiates melanin formation by enzymatic tyrosine hydroxylase and l-3,4-dihyroxyphenylalanine (DOPA) oxidase activities that are associated with its lumenal domain; a 5,6-dihydroxyindole oxidase activity, also a property of the tyrosinase lumenal domain, may contribute to a subsequent step in melanin synthesis (reviewed in Ref. 1.King R.A. Hearing V.J. Creel D.J. Oetting W.S. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. III. McGraw-Hill Inc., New York1995: 4353-4392Google Scholar). Lack of tyrosinase activity results in the absence of melanin formation due to the inability to form the melanin precursors, l-3,4-dihyroxyphenylalanine andl-3,4-dihyroxyphenylalanine quinone. OCA1 is a direct result of the absence or reduction of melanin.Different germline mutations within the tyrosinase coding region underlie OCA1 disorders of varying severity. In of OCA1 the mutations render tyrosinase temperature-sensitive melanin synthesis in of the the and The of pigmentation is to that of the and the PubMed Scopus Google Scholar, R.A. D. Oetting Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar). of ts of tyrosinase variant results a that at to a The the R402Q variant of tyrosinase is of the gene R.A. D. Oetting Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar). in transfected cells of the R402Q variant and the but variant that ts transfected cells grown at 37 °C of the tyrosinase enzymatic transfected cells grown at 31 °C with that of wild-type L.B. Tripathi R.K. King R.A. Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar, R.K. Hearing V.J. Spritz R.A. J. 1992; Full Text PDF PubMed Google Scholar). mutations that to a within the lumenal domain PubMed Scopus Google Scholar). the by mutations render the ts not enzyme activity is a of a defect at and of at reduced temperatures. at the may be that for are in the ts of 1991; PubMed Scopus Google Scholar) and J. 1995; PubMed Scopus Google Scholar). defects may be that the ts is at the J. J. 1996; PubMed Scopus Google in a of PubMed Scopus Google Scholar, J. 1992; PubMed Scopus Google Scholar, 1992; Full Text PDF PubMed Scopus Google Scholar, D. 1992; Full Text PDF PubMed Scopus Google Scholar). ts be to be for the The or and or for to and of R.A. 1993; PubMed Scopus Google Scholar, 1996; 381: PubMed Scopus Google for within the is the endoplasmic reticulum (ER) PubMed Scopus Google Scholar). Within the are by the activity of are and at are for to R.A. 1993; PubMed Scopus Google Scholar, Full Text PDF PubMed Scopus Google 1995; PubMed Scopus Google Scholar). that to are within the ER by or the the Full Text PDF PubMed Scopus Google Scholar). partially or ER and to be at of for by in J. 1996; PubMed Scopus Google Scholar, J. PubMed Scopus Google and to for degradation. Finally, may to and within late J. Med. 1996; PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar). be at within the ts with defects in be to be to or of ts gene that result in human and defects and the intracellular at the ts phenotype is in to we the localization and processing of the R402Q variant of human tyrosinase and show that the ts phenotype is due to a defect in that ER The ts phenotype of a wild-type allelic form of tyrosinase and the of in of the R402Q variant that the R402Q exaggerates in human tyrosinase expressed in non-melanogenic allelic of tyrosinase are the (2.Giebel L.B. Tripathi R.K. Strunk K.M. Hanifin J.M. Jackson C.E. King R.A. Spritz R.A. Am. J. Hum. Genet. 1991; 48: 1159-1167PubMed Google Scholar, R.A. D. Oetting Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar, L.B. Tripathi R.K. King R.A. Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R.A. Oetting W.S. Med. 1991; Google but the for ts phenotype not data that the ts enzymatic activities of the common R402Q of human tyrosinase R.K. Hearing V.J. Spritz R.A. J. 1992; Full Text PDF PubMed Google Scholar) are by and ER retention at the at 31 °C ER exit of at a of tyrosinase and subsequent to late or ER retention is a of ts in the PubMed Scopus Google Scholar, J. 1992; PubMed Scopus Google Scholar, 1992; Full Text PDF PubMed Scopus Google Scholar, D. 1992; Full Text PDF PubMed Scopus Google Scholar, R.A. 1993; PubMed Scopus Google and it is that ts allelic of tyrosinase this ts ER retention of tyrosinase in cells Y. D. V. PubMed Scopus Google cells may mutations the of or a ts allelic form of results that ER may be a for pigmentation and vision the ER retention of tyrosinase at the is a defect that The of the ER to that are in the ER 1996; 381: PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar). ts of the J. 1992; PubMed Scopus Google Scholar) and the PubMed Scopus Google in and are and in the ER at the but to ER at reduced temperatures. that the J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) and I J. PubMed Scopus Google may also and be the ER at reduced we for results for tyrosinase expressed in a of and J. F. that this is property of human that tyrosinase a partially at 37 °C that be at tyrosinase that at 37 °C be and by a subsequent to 31 °C. In the R402Q variant not be the R402Q or a that for tyrosinase, to in a J. J. 1996; PubMed Scopus Google Scholar). of the to or R402Q tyrosinase at 31 °C and of formation may to this its inability to be by a reduction in R402Q tyrosinase for a of in the that the variant of the glycoprotein PubMed Scopus Google of for with and R402Q of tyrosinase to be for by the in to tyrosinase in the of the These results of tyrosinase D.J. J. J. Med. PubMed Scopus Google Scholar, Y. D. V. PubMed Scopus Google Scholar). the and R402Q in ER to be in the of of the of tyrosinase to of that the of tyrosinase by this is and a of or R402Q tyrosinase is by this at These results that the ER of tyrosinase, for and with defects or partially to in the ER data that of and R402Q tyrosinase a a for degradation. The for ER the tyrosinase to and exit the tyrosinase to is by the by the R402Q is within the lumenal domain, it not that the R402Q tyrosinase lumenal domain ts ER the that the lumenal domain expressed a also ts for ER that the that to this variant within the ER are of the membrane of the tyrosinase is to in the of the membrane, tyrosinase be to the ER is are in a of are to ER or retention the form is to the ER is a in ER retention of and partially integral membrane and (reviewed in Ref. 1995; PubMed Scopus Google also PubMed Scopus Google and J. PubMed Scopus Google Scholar) and to ER retention of R402Q tyrosinase and of tyrosinase to be associated with a of tyrosinase in and cells Y. D. V. PubMed Scopus Google Scholar, J. D. V. 1993; PubMed Scopus Google Scholar, D. PubMed Scopus Google Scholar) and to be for tyrosinase in cells Y. J. PubMed Scopus Google tyrosinase that exits the ER in HeLa cells to be for in late and by the of in the sensitivity of this to and and the localization of tyrosinase to late and in HeLa cells at tyrosinase in cells of the melanocyte is to be Hearing V.J. J. Full Text Full Text PDF PubMed Scopus Google Scholar, Hearing V.J. PubMed Scopus (56) Google Scholar, S.J. J. 1995; PubMed Scopus Google Scholar). may for this tyrosinase may be to a in HeLa cells but not in cells. is by the of the of late and in cells but not in HeLa cells not and Ref. S.J. D.J. J. Invest. Dermatol. 1993; Full Text PDF PubMed Google Scholar). HeLa cells may a for tyrosinase in late endosomal is by the of tyrosinase in a melanocyte of the to a melanocyte Hearing V.J. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of the of tyrosinase in cells be to not tyrosinase but also tyrosinase in a and be by of of tyrosinase that in of the J. PubMed Scopus Google Scholar). be to this and to whether this a or is due to of tyrosinase in transfected results for the and of are mutations within the gene for tyrosinase that result in of the coding region for the the of tyrosinase and the defect in of the R402Q it is that of mutations not enzyme activity but the to be and in the The of tyrosinase in cells Y. D. V. PubMed Scopus Google Scholar) is due to a in cells mutations that the of tyrosinase is of tyrosinase in the ER may a common to pigmentation in OCA1 mutations in of the of enhanced or with J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) on the to of tyrosinase to whether to OCA1 Oculocutaneous albinism type 1 (OCA1)1comprises a group of human disorders characterized by reduced or absent skin pigmentation, vision defects due to reduced optical pigmentation and to misrouting of optic nerve fibers, and enhanced sensitivity to skin and optical cancers (1.King R.A. Hearing V.J. Creel D.J. Oetting W.S. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. III. McGraw-Hill Inc., New York1995: 4353-4392Google Scholar). These disorders are caused by germline mutations within the coding region of the melanocyte-specific gene product tyrosinase (2.Giebel L.B. Tripathi R.K. Strunk K.M. Hanifin J.M. Jackson C.E. King R.A. Spritz R.A. Am. J. Hum. Genet. 1991; 48: 1159-1167PubMed Google Scholar, 3.Tripathi R.K. Strunk K.M. Giebel L.B. Weleber R.G. Spritz R.A. Am. J. Med. Genet. 1992; 43: 865-871Crossref PubMed Scopus (56) Google Scholar, 4.Tomita Y. J. Invest. Dermatol. 1993; 100 (suppl.): 186-190Abstract Full Text PDF Scopus (21) Google Scholar). Tyrosinase, a key enzyme in the synthesis of melanin (reviewed in Ref. 5.del Marmol V. Beermann F. FEBS Lett. 1996; 381: 165-168Crossref PubMed Scopus (350) Google Scholar) is a type I integral membrane glycoprotein that is specifically expressed in cells of the melanocyte lineage, where it localizes to a specialized late endosome-like compartment, the melanosome (6.Orlow S.J. J. Invest. Dermatol. 1995; 105: 3-7Abstract Full Text PDF PubMed Scopus (235) Google Scholar). Within melanosomes, tyrosinase initiates melanin formation by enzymatic tyrosine hydroxylase and l-3,4-dihyroxyphenylalanine (DOPA) oxidase activities that are associated with its lumenal domain; a 5,6-dihydroxyindole oxidase activity, also a property of the tyrosinase lumenal domain, may contribute to a subsequent step in melanin synthesis (reviewed in Ref. 1.King R.A. Hearing V.J. Creel D.J. Oetting W.S. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. III. McGraw-Hill Inc., New York1995: 4353-4392Google Scholar). Lack of tyrosinase activity results in the absence of melanin formation due to the inability to form the melanin precursors, l-3,4-dihyroxyphenylalanine andl-3,4-dihyroxyphenylalanine quinone. OCA1 is a direct result of the absence or reduction of germline mutations within the tyrosinase coding region underlie OCA1 disorders of varying severity. In of OCA1 the mutations render tyrosinase temperature-sensitive melanin synthesis in of the the and The of pigmentation is to that of the and the PubMed Scopus Google Scholar, R.A. D. Oetting Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar). of ts of tyrosinase variant results a that at to a The the R402Q variant of tyrosinase is of the gene R.A. D. Oetting Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar). in transfected cells of the R402Q variant and the but variant that ts transfected cells grown at 37 °C of the tyrosinase enzymatic transfected cells grown at 31 °C with that of wild-type L.B. Tripathi R.K. King R.A. Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar, R.K. Hearing V.J. Spritz R.A. J. 1992; Full Text PDF PubMed Google Scholar). mutations that to a within the lumenal domain PubMed Scopus Google Scholar). the by mutations render the ts not ts enzyme activity is a of a defect at and of at reduced temperatures. at the may be that for are in the ts of 1991; PubMed Scopus Google Scholar) and J. 1995; PubMed Scopus Google Scholar). defects may be that the ts is at the J. J. 1996; PubMed Scopus Google in a of PubMed Scopus Google Scholar, J. 1992; PubMed Scopus Google Scholar, 1992; Full Text PDF PubMed Scopus Google Scholar, D. 1992; Full Text PDF PubMed Scopus Google Scholar). ts be to be for the The or and or for to and of R.A. 1993; PubMed Scopus Google Scholar, 1996; 381: PubMed Scopus Google Scholar). The for within the is the endoplasmic reticulum (ER) PubMed Scopus Google Scholar). Within the are by the activity of are and at are for to R.A. 1993; PubMed Scopus Google Scholar, Full Text PDF PubMed Scopus Google 1995; PubMed Scopus Google Scholar). that to are within the ER by or the the Full Text PDF PubMed Scopus Google Scholar). partially or ER and to be at of for by in J. 1996; PubMed Scopus Google Scholar, J. PubMed Scopus Google and to for degradation. Finally, may to and within late J. Med. 1996; PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar). be at within the ts with defects in be to be to or of ts gene that result in human and defects and the intracellular at the ts phenotype is in to we the localization and processing of the R402Q variant of human tyrosinase and show that the ts phenotype is due to a defect in that ER The ts phenotype of a wild-type allelic form of tyrosinase and the of in of the R402Q variant that the R402Q exaggerates in human tyrosinase expressed in non-melanogenic cells. allelic of tyrosinase are the (2.Giebel L.B. Tripathi R.K. Strunk K.M. Hanifin J.M. Jackson C.E. King R.A. Spritz R.A. Am. J. Hum. Genet. 1991; 48: 1159-1167PubMed Google Scholar, R.A. D. Oetting Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar, L.B. Tripathi R.K. King R.A. Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R.A. Oetting W.S. Med. 1991; Google but the for ts phenotype not data that the ts enzymatic activities of the common R402Q of human tyrosinase R.K. Hearing V.J. Spritz R.A. J. 1992; Full Text PDF PubMed Google Scholar) are by and ER retention at the at 31 °C ER exit of at a of tyrosinase and subsequent to late or ER retention is a of ts in the PubMed Scopus Google Scholar, J. 1992; PubMed Scopus Google Scholar, 1992; Full Text PDF PubMed Scopus Google Scholar, D. 1992; Full Text PDF PubMed Scopus Google Scholar, R.A. 1993; PubMed Scopus Google and it is that ts allelic of tyrosinase this ts ER retention of tyrosinase in cells Y. D. V. PubMed Scopus Google cells may mutations the of or a ts allelic form of results that ER may be a for pigmentation and vision the ER retention of tyrosinase at the is a defect that The of the ER to that are in the ER 1996; 381: PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar). ts of the J. 1992; PubMed Scopus Google Scholar) and the PubMed Scopus Google in and are and in the ER at the but to ER at reduced temperatures. that the J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) and I J. PubMed Scopus Google may also and be the ER at reduced we for results for tyrosinase expressed in a of and J. F. that this is property of human that tyrosinase a partially at 37 °C that be at tyrosinase that at 37 °C be and by a subsequent to 31 °C. In the R402Q variant not be the R402Q or a that for tyrosinase, to in a J. J. 1996; PubMed Scopus Google Scholar). of the to or R402Q tyrosinase at 31 °C and of formation may to this its inability to be by a reduction in R402Q tyrosinase for a of in the that the variant of the glycoprotein PubMed Scopus Google of for with and R402Q of tyrosinase to be for by the in to tyrosinase in the of the These results of tyrosinase D.J. J. J. Med. PubMed Scopus Google Scholar, Y. D. V. PubMed Scopus Google Scholar). the and R402Q in ER to be in the of of the of tyrosinase to of that the of tyrosinase by this is and a of or R402Q tyrosinase is by this at These results that the ER of tyrosinase, for and with defects or partially to in the ER data that of and R402Q tyrosinase a a for degradation. The for ER the tyrosinase to and exit the tyrosinase to is by the by the R402Q is within the lumenal domain, it not that the R402Q tyrosinase lumenal domain ts ER the that the lumenal domain expressed a also ts for ER that the that to this variant within the ER are of the membrane of the tyrosinase is to in the of the membrane, tyrosinase be to the ER is are in a of are to ER or retention the form is to the ER is a in ER retention of and partially integral membrane and (reviewed in Ref. 1995; PubMed Scopus Google also PubMed Scopus Google and J. PubMed Scopus Google Scholar) and to ER retention of R402Q tyrosinase and of tyrosinase to be associated with a of tyrosinase in and cells Y. D. V. PubMed Scopus Google Scholar, J. D. V. 1993; PubMed Scopus Google Scholar, D. PubMed Scopus Google Scholar) and to be for tyrosinase in cells Y. J. PubMed Scopus Google tyrosinase that exits the ER in HeLa cells to be for in late and by the of in the sensitivity of this to and and the localization of tyrosinase to late and in HeLa cells at tyrosinase in cells of the melanocyte is to be Hearing V.J. J. Full Text Full Text PDF PubMed Scopus Google Scholar, Hearing V.J. PubMed Scopus (56) Google Scholar, S.J. J. 1995; PubMed Scopus Google Scholar). may for this tyrosinase may be to a in HeLa cells but not in cells. is by the of the of late and in cells but not in HeLa cells not and Ref. S.J. D.J. J. Invest. Dermatol. 1993; Full Text PDF PubMed Google Scholar). HeLa cells may a for tyrosinase in late endosomal is by the of tyrosinase in a melanocyte of the to a melanocyte Hearing V.J. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of the of tyrosinase in cells be to not tyrosinase but also tyrosinase in a and be by of of tyrosinase that in of the J. PubMed Scopus Google Scholar). be to this and to whether this a or is due to of tyrosinase in transfected results for the and of are mutations within the gene for tyrosinase that result in of the coding region for the the of tyrosinase and the defect in of the R402Q it is that of mutations not enzyme activity but the to be and in the The of tyrosinase in cells Y. D. V. PubMed Scopus Google Scholar) is due to a in cells mutations that the of tyrosinase is of tyrosinase in the ER may a common to pigmentation in OCA1 mutations in of the of enhanced or with J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) on the to of tyrosinase to whether to OCA1 ts allelic of tyrosinase are the (2.Giebel L.B. Tripathi R.K. Strunk K.M. Hanifin J.M. Jackson C.E. King R.A. Spritz R.A. Am. J. Hum. Genet. 1991; 48: 1159-1167PubMed Google Scholar, R.A. D. Oetting Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar, L.B. Tripathi R.K. King R.A. Spritz R.A. J. Invest. 1991; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R.A. Oetting W.S. Med. 1991; Google but the for ts phenotype not data that the ts enzymatic activities of the common R402Q of human tyrosinase R.K. Hearing V.J. Spritz R.A. J. 1992; Full Text PDF PubMed Google Scholar) are by and ER retention at the at 31 °C ER exit of at a of tyrosinase and subsequent to late or ER retention is a of ts in the PubMed Scopus Google Scholar, J. 1992; PubMed Scopus Google Scholar, 1992; Full Text PDF PubMed Scopus Google Scholar, D. 1992; Full Text PDF PubMed Scopus Google Scholar, R.A. 1993; PubMed Scopus Google and it is that ts allelic of tyrosinase this ts ER retention of tyrosinase in cells Y. D. V. PubMed Scopus Google cells may mutations the of or a ts allelic form of results that ER may be a for pigmentation and vision the The ER retention of tyrosinase at the is a defect that The of the ER to that are in the ER 1996; 381: PubMed Scopus Google Scholar, 1995; PubMed Scopus Google Scholar). ts of the J. 1992; PubMed Scopus Google Scholar) and the PubMed Scopus Google in and are and in the ER at the but to ER at reduced temperatures. that the J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) and I J. PubMed Scopus Google may also and be the ER at reduced we for results for tyrosinase expressed in a of and J. F. that this is property of human that tyrosinase a partially at 37 °C that be at tyrosinase that at 37 °C be and by a subsequent to 31 °C. In the R402Q variant not be the R402Q or a that for tyrosinase, to in a J. J. 1996; PubMed Scopus Google Scholar). of the to or R402Q tyrosinase at 31 °C and of formation may to this its inability to be by a reduction in R402Q tyrosinase for a of in the that the variant of the glycoprotein PubMed Scopus Google Scholar). of for with and R402Q of tyrosinase to be for by the in to tyrosinase in the of the These results of tyrosinase D.J. J. J. Med. PubMed Scopus Google Scholar, Y. D. V. PubMed Scopus Google Scholar). the and R402Q in ER to be in the of of the of tyrosinase to of that the of tyrosinase by this is and a of or R402Q tyrosinase is by this at These results that the ER of tyrosinase, for and with defects or partially to in the ER data that of and R402Q tyrosinase a a for degradation. The for ER the tyrosinase to and exit the tyrosinase to is by the by the R402Q is within the lumenal domain, it not that the R402Q tyrosinase lumenal domain ts ER the that the lumenal domain expressed a also ts for ER that the that to this variant within the ER are of the membrane of the tyrosinase is to in the of the membrane, tyrosinase be to the ER is are in a of are to ER or retention the form is to the ER is a in ER retention of and partially integral membrane and (reviewed in Ref. 1995; PubMed Scopus Google also PubMed Scopus Google and J. PubMed Scopus Google Scholar) and to ER retention of R402Q tyrosinase and of tyrosinase to be associated with a of tyrosinase in and cells Y. D. V. PubMed Scopus Google Scholar, J. D. V. 1993; PubMed Scopus Google Scholar, D. PubMed Scopus Google Scholar) and to be for tyrosinase in cells Y. J. PubMed Scopus Google Scholar). tyrosinase that exits the ER in HeLa cells to be for in late and by the of in the sensitivity of this to and and the localization of tyrosinase to late and in HeLa cells at tyrosinase in cells of the melanocyte is to be Hearing V.J. J. Full Text Full Text PDF PubMed Scopus Google Scholar, Hearing V.J. PubMed Scopus (56) Google Scholar, S.J. J. 1995; PubMed Scopus Google Scholar). may for this tyrosinase may be to a in HeLa cells but not in cells. is by the of the of late and in cells but not in HeLa cells not and Ref. S.J. D.J. J. Invest. Dermatol. 1993; Full Text PDF PubMed Google Scholar). HeLa cells may a for tyrosinase in late endosomal is by the of tyrosinase in a melanocyte of the to a melanocyte Hearing V.J. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of the of tyrosinase in cells be to not tyrosinase but also tyrosinase in a and be by of of tyrosinase that in of the J. PubMed Scopus Google Scholar). be to this and to whether this a or is due to of tyrosinase in transfected cells. results for the and of are mutations within the gene for tyrosinase that result in of the coding region for the the of tyrosinase and the defect in of the R402Q it is that of mutations not enzyme activity but the to be and in the The of tyrosinase in cells Y. D. V. PubMed Scopus Google Scholar) is due to a in cells mutations that the of tyrosinase is of tyrosinase in the ER may a common to pigmentation in OCA1 mutations in of the of enhanced or with J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) on the to of tyrosinase to whether to OCA1 and for of