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Tyrosinase Causing Oculocutaneous Albinisms

Yasushi Tomita Department of Dermatology,Tohoku University School of Medicine,Sendai,japan

Since the firstreport of a in the gene that y, produce with no activity and with very causes tyrosinase-negative oculocutaneous albinism (OCA), low activity, respectively.The third, termed ts,produces tem­ more than 25 alleles with a different mutation in patients perature-sensitive tyrosinase with very low activity at 35°C, with three types of OCA, i.e., tyrosinase-negative OCA but with no activity at temperatures greater than 35°C. (type IA), yellow-mutant OCA (type m), and temperature Various combinations of these alleles result in tyrosinase-ne­ sensitive OCA (type ITS), have been found in several labora­ gative (r/r), yellow mutant (y/y, y/r, y/ts), or tempera­ tories. The mutated alleles are presendy classified into three ture-sensitive (ts/r, ts/ts)OCA.JlnvestDermatoI100:186S- types. The firstan d the second group of alleles, termed r and 1905, 1993

culocutaneous albinism (OCA), characterized by a sinase gene is normal in type II, which, therefore, results from a decrease in pigment in the skin, hair, and defect in unknown gene(s). Both types of OCA have autosomal eyes, comprises a heterogeneous group of inherit­ recessive inheritance [I). able disorders. Witkopet al [1) described 10 typesof At present, type I OCA is subdivided into three types. The firstis OCA of which type IA (tyrosinase-negative albi­ tyrosinase-negative OCA (type IA),which is completely lacking in nos)O and type IB (yellow mutant albinos) are due to no or low tyrosinase activity and therefore shows no melanin formation dur­ activityof tyrosinase. Tyrosinase, which catalyzes the conversion of ing the of the patient, i.e., its phenotype is white hair and skin, to dihydroxyphenylalanine (dopa), is a key enzyme for and red eyes throughout life [1). The second type is yellow-mutant melanin in pigment cells [2). Recent progress in molec­ OCA (type IB), which shows little pigment at birth but rapidly ular has made it possible to isolate tyrosinase from develops yellow hair pigment in the first few years of life and then normal subjects and albino patients and to determine their nucleo­ continues with a slow accumulation of pigment in the hair, eyes, tide sequences. By comparing patients' sequences with those of and skin over time. The hair bulbs of a patient with yellow OCA normal subjects, it has become possible to clarify many mutations show the presence of tyrosinase but with very low activity [I). The causing various types of albinism. third type is a newly described one, namely, temperature-sensitive In 1986, Shibahara et al [3) reported a mouse tyrosinase cDNA OCA (type ITS) [9J. A patient with type ITS has white skin, blue clone candidate, pMT4, and in 1987 Kwonetal[4) and Yamamoto irises, and white axillary and scalp hair, but has lightly pigmented et al [5) cloned tyrosinase cDNA, Pmel34, and Tyrs-33 from the arm hair, anddark brown leg hair. Melanin production is dependent human and the mouse, respectively. As these cDNA clones are on the skin temperature in each area of the patient's body [9); the similar to, but definitely different from, each other in their nucleo­ warm areas have no pigment but the cooler areas do have pigment. tide sequences, there was some confusion and disagreement All three subtypes result from different mutations of the tyrosinase whether there might be several of tyrosinase. In 1988, gene, which have been clarified in these three years. Ruppertet al [6) and Mulleret at [7) determined that pMT4 encodes a Tyrosinase-positive OCA (type II) is thought to result from at the b-Iocus, termed "tyrosinase-related protein" by Jack­ various gene defects, because its phenotypes are various. The lack of [8), and that pmel34 encodes human tyrosinase, whereas Tyrs- molecular characterization prevents the classification of type II 33 is one of three cDNAs resulting from alternative splicing of the OCA and the clarification of their pathogeneses. Therefore, only primary transcript of a single tyrosinase. Since then, many re­ type I OCA will be addressed in this review. searchers have been attempting to clarify the pathologic mutations TYROSINASE cDNA AND ITS DEDUCED AMINO that cause tyrosinase-related albinism. SEQUENCE In this review, the pathologic mutations found in tyrosinase genes of OCA patients are described and the relationship between Human tyrosinase cDNA, pmel34, was cloned and its genotypes and phenotypes of various OCA explained. sequence was reported by Kwon et at in 1987 [4). Recently, they have corrected their initially reported sequence of pmel34 [10). We CLASSIFICATION OF OCA have also isolated human tyrosinase cDNA, pHTI'I, using a syn­ Human OCA is classified into two major types, tyrosinase related thetic oligonucleotide complementary to a segment of pmel34 and (type I) and tyrosinase positive (type II) OCA. Type I results from determined the sequence of tyrosinase cDNA for comparison with abnormalities of the tyrosinase gene. On the other hand, the tyro- .sequences of albino patients to find new mutations ofthe tyrosinase 'gene [11). The sequence deduced from humantyrosinase cDNA Reprintreq uests to: Dr. Yasushi Tomita, Departmentof Dermatology, Tohoku UniversitySchool of Medicine,1-1 Seiryomachi,Aobaku, Sendai is shown in Fig 1. It is composed of 529 amino and the first18 980, Japan. amino acid residues at the N-terminal region constitute a signal Abbreviation: [11,12). Secretory and membrane-associated usu­ OCA: oculocutaneous albinism ally contain a that enables such proteins to cross a

0022-202X/93/S06.00 Copyright © 1993 by The Society for Investigative Dermatology, Inc.

186S VOL. 100, NO.2, SUPPLEMENT, FEBRUARY 1993 TYROSINASE GENE MUTATIONS IN ALBINISMS 187S

· . . . . . 1 MLLAVLYCLLWSI'QTSAGIII'PRACVSSKNLMEKECCPPWSGDRSPCGQLSGRGSCQNILL (-18) (1) 2 3 4 5 · . . . . . 61 SNAPLGPQI'PI'TGVDDRESWPSVI'YNRTCQCSGNFMGI'NCGNCKFGFWGPNCTERRLLVR ------U.o: (43) -l� ��rR-o-R-m-RDR-{)]- · . . . . . 121 RNIFDLSAPEKDKFFAYLTLAKITTISSDYVIPIGTYGQMKNGSTPMFNDINIYDLl'VIVMH 272 273 345 346 395 396 455 456 529 (103)

181 YYVSMDALLGGSEIWRDIDFAHEAPAFLPIYITRLFLLRWEClEIQKLTGDENl'TIPYlVDWRD Figure 2. of the human tyrosinase gene. The five boxes (1-5) (163) represent the five of the tyrosinase gene [11,26]. Numbers under · . . . . . 241 AEKCDICTDEYMGGQIIPTNPNLLSPASFFSSWQIVCSRLEEYNSIIQSLCNGTPEGPLRRN the boxes represent the codon number of the firstor the last codon of each (223) .lEiI,putative -binding region.• , thetransmembrane segment. 301 PGNHDKSihpRI.PSSADVEFCLSL TQYESGSMDKAAN FSFL!NTLEGFAS PL TG IADIISQS (283)

361 SMLLNIlLILIY�1NGTMSQVQGSANDPIFLLLLiLAFVDSIFEQWLHRHRPLQEVYrEANArIG. ;! (343)

· . . . . . 421 NRESYMVrFIPLYRNGDl'l'ISSKDLGYDYSYLQDSDPDSFQDYIKSYLEQASRIWSWLLG ••••••• groups [7,22-25]. The amino acid between (403) mouse tyrosinase and human tyrosinase is about 86% [11]. 481 AIIMVGIIVLTALLAGLVSLLCRLLKRKQLPEEKQPLLMEKEDYITSLYQSIlL 529 (463)··················· (511) TYROSINASE GENE

Figure 1. Amino acid sequence of human tyrosinase deduced from its We have cloned and sequenced the genomic DNA segment of the eDNA. The deduced amino acidsare shownby single-lettercodes and are protein obtained from the human tyrosinase gene numbered starting from the amino-terminal of the transcribed [11,26]. The human tyrosinase gene is organized into fiveexons, as tyrosinase [11]. The numbers in parentheses are those starting from the shown in Fig 2, and its size is thought to be more than 70 kb [11,27]. amino-terminal residue of the mature tyrosinase and the preceding resi­ These findingswere confirmedby Giebel et al [16]. Barton et al [28] due of a signal peptide isindicated by a negative number. The additional arm aminoacids (Y at 192, T at 308, Q at 402, and P at 495) are reported to be reported that the tyrosinase gene is localized in the long of non-pathologicpolymorphisms. Putative copper-binding regionsare un­ chromosome 11 in region 11q14-q21. The con­ derlined.Asterisks, transmembrane segments. tains additional sequences cross-hybridizing to the exon 4 and exon 5 tyrosinase gene [29], mapped to the short arm of chromosome 11, near the centromere (pl1.2-cen) [28]. The additional sequences are tyrosinase pseudo genes, which share more than 98% nucleotide homology with exon 4 and exon 5 of the human tyrosinase gene membrane, and the peptide is removed duringthe process [13,14]. [16,29,30]. The melanosome-bound form of mature tyrosinase, which removes The nucleotide sequence of the promoter region located up­ the 18 amino acids of the signal peptide, is thus composed of 511 stream fromthe tyrosinase coding region and its function have been amino acids, having a molecular weight of 58,000, with at partially elucidated [16,31]. the N-terminal [11], as confirmed by the analysis of its aminoacid TYROSINASE GENE MUTATION sequence by Wittbjer et al [15]' Recently Giebel et al [16], and Bouchard et al [17] have reported In 1989 we found a pathologic mutation of the tyrosinase gene for that several common non-pathologic polymorphisms in the tyro­ the first time in a patient with oculocutaneous albinism [26]. Since sinase geneare found in Caucasians, and these cause an alteration of then a number of various mutations have been reported by several the amino acids at 192 and 402 as shown in Fig 1. Chintamaneni et al research groups [10,18,27,32-42] as summarized in Table I. All of [10] have also described two other polymorphisms that alter the these mutations are located in the protein coding region, but none in amino acids at 308 and 495 (Fig 1). the promoter region. They are classifiedinto several kindsof muta­ When we previously reported the nucleotide sequence of tyro­ tions, i.e., a , a , and a frame sinasecDNA, we numbered the codons starting from the codon of shift mutation. A missense mutation denotes an alteration of one histidine, the N-terminal of mature tyrosinase, because the se- nucleotide that causes a codon specific for a given amino acid to 9uence of the signal was not fullydetermined at that time specify another amino acid. On the other hand, the change to a [11]. However, many researchers have recently adopted a system of termination codon such as TAA, TAG, and TGA at which the numbering from the N-terminal of the signal peptides [18], thus protein synthesis on the stops is known as a nonsense making it somewhat difficult to compare the sites of point muta­ mutation. Frame-shift mutations found in the tyrosinase gene as tionswe found in the tyrosinase gene of albino patients with the shown in Table I are a single-base , or a single/double/four ones they found. We would therefore like to renumber the codons base deletion in the coding region that causes the frame shift of of tyrosinasecDNA in accordance with the system now more com­ triplets (codons) and finallyintroduces a termination codon. Four of monly employed, starting from the N-terminal of the signal pep­ seven insertion/deletion mutations found in OCA patients reside tides at which 18 amino acids have already been confirmed, as within repetitive base sequences, i.e., CCCC [26], GGGGG [36], shown in Fig 1. GTGTG [36], and CTTT [42]. Streisinger et al [43,44] have sug­ Tyrosinase is known to have two Cu++ [19] and we tentatively gested that the repetitive sequence allows slippage and misalign­ assigntwo regions, amino acid residues 172-238 and 361-403, as ment of the two DNA strands, with a looping out of one or more the copper-binding sites [11]. At each copper-binding site, three or bases, and subsequent DNA synthesis would then either omit or add four histidine residues are present, and some of them conceivably a nucleotide or nucleotide pair. serveas the ligands of the two of tyrosinase. Mature tyrosin­ New tyrosinase proteins arising by missense mutations contain ase contains 16 residues, which are probably involved in the only single amino acid replacements. However, they are character­ constructionof the tertiary structure of the protein. There are six ized by various extents of tyrosinase activity that can be classified potential N- sites, which are residues. Be­ into four groups (Table II). The firstgroup consists of mutations in cause human tyrosinase contains four asparagine-linked sugar which tyrosinase activity remains as high as that of the original one; chains per molecule [20], some of these residues are functionalN­ this group of alleles belongs to a wild allele termed T+, and can glycosylation sites. This glycosylation is linked with the transfer of therefore be regarded as a polymorphismbecause it has no patho­ tyrosinase from the rough to the melano­ logic significance. Many nonpathologic polymorphisms in the some via the Golgi complex [21]. Human tyrosinase also contains a human tyrosinase gene have already been reported [16,17]. The putative transmembrane segment near the carboxyl terminus (resi­ second group of mutated alleles, the tyrosinase of which completely dues 474-499) [11]. loses its enzyme activity, is tentatively termed t-. In the third Mouse tyrosinase cDNA has been isolated by several research group, the alleles termed y produce with very low activity. 188S TOMITA THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Table I. Mutations Associated with Tyrosinase-Related DCA Number of Amino Type of Codon Acid of Mature Nucleotide Amino Acid Allele (No.) Tyrosinase Exon Substitution Substitution" References

t- 42 24 1 GAC�GGC Asp(D) � Gly(G) [41] C 47 29 1 GGC�GAC Gly(G) �Asp(D) [32] t- 55 37 1 TGT�TAT Cys(C) � Tyr(Y) [41] C 77 59 1 CGG�CAG Arg(R)� Gln(Q) [27,33] C 81 63 1 ccr�CTI Pro(P)--+ Leu(L) [34] t- 89 71 1 TGC�CGC Cys(C)--+ Arg(R) [35] t- 96 78 1 ATG�AATG Term168 [36] t- 176 158 1 TIT--+ATT Phe(F)--+ ne(I) [42] t- 178 160 1 TGG--+TAG Trp(W)--+ Term [37] C 191 173 1 GGAT�GAT Term 225 [36] C 206 188 1 GCT�ACT Ala(a)--+ Thr(T) [41] C 217 199 1 CGG�CAG Arg(R)--+ Gln(Q) [42] t- 244 226 1 TGTGA�TGA Term 244 [36] y 275 257 2 GTC�TIC Val(V)--+ Phe(F) [38] C 310 292 2 CCA�CCCA Term 317 [26] C 371 353 3 AAT�Acr Asn(N)--+ Thr(T) [32] t- 373 355 3 ACA�AAA Thr(T)--+ Lys(K) [39] t- 378 360 3 CAG�TAG Gln(Q) �Term [42] t- 382 364 3 AAC�AAA Asn(N)--+ Lys(K) [36] t- 383 365 3 GAT�AAT Asp(D)� Asn(N) [39] y 406 388 4 ccr�CTI Pro(P)--+ Leu(L) [38] t- 419 401 4 GGA�AGA Gly(G)--+ Arg(R) [41] 15 422 404 4 CGG�CAG Arg(R)� Gln(Q) [40] t- 438 420 4 Delete CTTT Term 484 [42] C 453 435 4 CAA�TAA Gln(Q) �Term [42] t- 490 472 5 GCC�TGCC Term 509 [10] C 501 483 5 CGT�CCGT Term509 [38]

• Term, termination signal.

In the fourth, the allele termed ts produces enzyme with very low alleles, as shown in Table III. A person with one allele of the wild activity at 31°C, but decreasing to almost no activity around 37°C. tyrosinase gene (r+) always expresses normal skin pigmentation Half of the missense mutations found in 16 c alleles localize in even if the other allele is r, y, or ts. That is, the subject is a carrier two copper-binding regions (codon 172- 238 and codon 361-403) (heterozygous) of the mutated gene, which means that melanin and a substituted amino acid is assumed to change the steric confor­ production is fully realizedby half the amount of tyrosinasesynthe­ mation at the copper-binding site or at the of the enzyme, sized in a normally pigmented person. which can then completely inhibit its catalytic function.Most of the In a patient with tyrosinase-negative DCA, melanin formation other missense mutations are in exon 1 (Table I) and, at present, no never occurs throughout the patient's life [1] because the patient's one can explain why or how substituted amino acids, eg, genotype is homozygous r allele [10,18,26,27,32-37,39,41]. from and from·, change the tertiary Yellow mutant albino patients completely lack detectable pig­ structureof the enzyme protein into an inactive form except for the ment at birth and are initially indistinguishable frompatients with case of tyrosine/arginine substitution from cysteine whose side tyrosinase-negative OCA. However, patients with yellow mutant group "SH" usually involves the stereochemical structure of pro­ OCA accumulate some melanin pigment, principally yellow-red tein. pheomelanin, during childhood and adulthood [1,38]. The geno­ There have been several reports of insertion or deletion mutations type of yellow mutant OCA is reported to be y X r; that is, the of tyrosinase gene, all of them inducing a nonsense codon that patient has very low tyrosinase activity [38]. The reason melanin produces incomplete tyrosinase protein with no activity (Table I). accumulation develops with the patient's growth is unclear. A pa­ These also can be classified into the second group, r (Table II). tient with homozygous y allele has also been reported [38], the phenotype also being yellow mutant DCA. GENOTYPES AND PHENOTYPES A patient with temperature-sensitive OCA analogous to that of DF VARIOUS OCA the Siamese and the Himalayan mouse has been recently re­ Three types of OCA caused by tyrosinase gene mutations are now ported by King et al [9]. The patient had white hair and skin, and known, i.e., type IAOCA [1], yellow mutant (type IB) OCA [1,38], blue eyes at birth, and a diagnosis of OCA was made. At puberty, she and temperature-sensitive OCA (type ITS) [9,40J. These three phe­ notypes genetically atise from various combinations of the three Tablem. Relation between Genotype and DCA Phenotype

Allele T+ t- Y 15 Table D. Alleles of Tyrosinase and the Enzyme Activity of T+ Normal Normal Normal Normal Their Products (T+/T+) (T+/q (T+/y) (T+ /15) Tyrosinase Activity t- Normal ty-neg ym tern-sen Allele in Product (t-/T+) (t-/q (t-/y) (t-/15) y Normal ym ym ym T+ High (y/T+) (y/q (y/y) (y/15)" C None 15 Normal tern-sen ym tern-sen Y Very low (15/T+) (15/C) (15/y)" (15/15)" 15 Very low at 35°C None at 37°C • No patientwith the indicated genotype hasyet been detected. ty-neg, tyrosinase- negative OCA; ym, yellow mutant OCA; tern-sen, temperature·sensitive OCA. VOL. 100, NO.2, SUPPLEMENT, FEBRUARY 1993 TYROSINASE GENE MUTATIONS IN ALBlNlSMS 1898

developed progressively darker hair in the cooler areas(extremities), 11. Shibahara S,Tomita Y,Tagami H,Miiller RM, Cohen T: Molecular but retained white hair in the warmer areas (scalp and axilla) [9]. basis for the heterogeneity of humantyrosinase. Tohoku J Exp Med This clinical feature is explained genetically as follows. The pa­ 156:403-414,1988 tient's genotype is ts X r; the ts gene produces temperature-sensi­ 12. Takeda A,Tomita Y,Okinaga A,Tagarni H,Shibahara S: Functional tive tyrosinase, which has very low activity at 35°C and loses its analysis of the cDNA encoding human tyrosinase precursor. Bio­ activity above 35 ° C, whereas the r gene produces inactive tyrosin­ chern Biophys Res Commun 162:984-990,1989 ase [35]. A patient with homozygous ts may be also diagnosed as 13. Blobel G, Dobberstein B: Transfer of proteins across membranes. J having yellow mutant OCA, but a patient with ts X Y would proba­ Bioi 67:852-862,1975 bly be diagnosed as suffering from yellow mutant OCA. However, 14. Steiner DF,Quinn PS,Chan SJ,Marsh J,Tager HS: Processing mecha­ there have been no reports of such cases to date. nisms in the biosynthesis of proteins. Ann NY Acad Sci 343:1-16, Patients with tyrosinase-positive OCA have more or less tyrosin­ 1980 ase activity in their . Therefore, this type of OCA .is 15. Wittbjer A,Odh G,Rosengren A-M,Rosengren E,Rorsman H: Isola­ thought to be due to a defect of factors involving melanogenesis tion of soluble tyrosinase from human melanoma. Acta Derm Ven­ ereol (Stockh) 70:291-294,1990 other than tyrosinase. There must be heterogeneous causes of tyro­ sinase-positive OCA, because its clinical features are so various: 16. Giebel LB, Strunk KM, Spritz RA: Organization and nucleotide se­ quences of the human tyrosinasegene and a truncated tyrosinase-re­ some atients already have yellow or blond hair at birth, whereas p lated segment. 9:435-445,1991 some have white hair throughout their . We checked the tyro­ sinase geneof one patient with tyrosinase-positive OCA, but found 17. Bouchard B,Fuller BB,Vijayasaradhi S,Houghton AN: Induction of pigmentation in mouse fibroblasts by expression of human tyrosin­ no mutation [45]. However, I believe that a subtype of tyrosinase­ ase cDNA. J Exp Med 169:2029-2042,1989 positive OCA exists that is caused by a frame-shift mutation at the 18. OettingWS, Handoko HY,Mentink MM, Paller AS,White JG,King membrane binding region of tyrosinase, which causes the reading RA:Molecular analysis of an extended family with type IA (tyrosin­ to shiftand the amino acid sequence of the membrane binding frame ase-negative) oculocutaneous albinism. J Invest Dermatol 97:15- region to change. Such tyrosinase probably has enough enzyme 19, 1991 activity but cannot bind with the melanosome membrane, resulting 19. Nishioka K: Particulate tyrosinase of human malignant melanoma. in the non-occurrence of physiologic melanogenesis in the patient's Eur J Biochem 85:137-146,1978 The region from the transmembrane to the carboxyl melanocytes. 20. Ohkura T ,Yamashita K,Mishima Y,Kobata A: Purification of ­ terminal of tyrosinase is not crucial for the enzyme activity because ster melanoma tyrosinase and structural studies of their asparagine­ of the membrane-bound tyrosinase results in a linked sugar chains. Arch Biochem Biophys 235:63-77,1984 soluble tyrosinase with full enzyme activity [15]. 21. Imokawa G,Mishima Y: Functional analysis of tyrosinase isozymes of The molecular bases of OCA caused by tyrosinase gene mutation cultured malignant melanoma cells during the recovery fol­ have been rapidly clarified over the past three years as described in lowing interrupted melanogenesis induced by glycosylation inhibi­ this review. For the future, the systematic procedure of gene diag­ tors. J Invest DermatoI83:196-201,1984 nosis in various types of tyrosinase-related OCA is expected to be 22. Kwon BS, Haq AK, Pomerantz SH,Halaban R: Sequence analysis of well established. mouse tyrosinase cDNA and the effect of melanotropin on its . Biochem Biophys Res Commun 153:1301-1309, 1988 23. Yamamoto H, Takeuchi S, Kudo T, Sato C, Takeuchi T: Melanin production in cultured albino melanocytes transfected with mouse REFERENCES tyrosinase cDNA. Jpn J Genet 64:121-135,1989 1. Witkop Jr CJ, Quevedo Jr WC,Fitzpatrick TB, King RA: Albinism. 24. 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a direct sequencing of amplified DNA. Hum Genet 85:123 -124, gene mutationin a patient with type IA oculocutaneous albinism. N 1990 Engl J Med 322:1724-1728,1990

34. Giebel LB, Strunk KM, King RA, Hanifin JM,Spritz RA: A frequent 40. Giebel LB,Tripathi RK, King RA, Spritz RA: A temperature-sensitive tyrosinase gene mutation in classic, tyrosinase-negative (type IA) tyrosinasein human albinism: a human homologue to the Siamese oculocutaneous albinism. Proc Nat! Acad Sci USA 87:3255-3258, cat and the Himalayan mouse. J Clin Invest 87:1119-1122, 1991

1990 41. King RA, Mentink MM, Oetting WS: Non-random distribution of 35. Spritz RA, Strunk KM, Hsieh C-L, Sekhon S, Francke U: Homozy­ missense mutations within the human tyropsinase gene in type I gous tyrosinase gene mutation in an American Black with tyrosin­ (tyrosinase-related) oculocutaneous albinism. Mol BioI Med 8:19- ase-negative (type IA) oculocutaneous albinism. Am J Hum Genet 29,1991 48:318-324,1991 42. King RA, Oetting WS: Molecular analysis of type IA(tyrosinase nega­ 36. Oetting WS,Mentink MM , Summers CG,Lewis RA, White JG,King tive) oculocutaneous albinism (abstr). J Invest Dermatol 98:646, RA: Three different frameshift mutations of the tyrosinase gene in 1992 type IA oculocutaneous albinism. Am J Hum Genet 49:199-206, 43. Streisinger G, Okada Y,Emrich J,Newton J,Tsugita A,Teraghi E, 1991 Inoue M: Frameshift mutations and the genetic . Cold Spring 37. Giebel LB, Musarella MA, Spritz RA: A nonsense mutation in the Harbor Symp Quant BioI 31:77-84,1966 tyrosinase gene of Afghan patients with tyrosinase-negative (type 44. Streisinger G, Owen JE: Mechanisms of spontaneous and induced IA) oculocutaneous albinism. J Med Genet 28:464-467,1991 in bacteriophage T4. 109:633-659, 38. Giebel LB,Tripathi RK, Strunk KM, HanifinJM, Jackson CE,King 1985 RA, Spritz RA: Tyrosinase gene mutation associated with type m 45. Matsunaga J,Takeda A,Tomita Y,Hara M,Shibahara S,Tagami H: ("yellow") oculocutaneous albinism. Am J Hum Genet 48: 1159- Cloning and sequence analysis of the tyrosinasegene froma patient 1167, 1991 with tyrosinase-positive oculocutaneous albinism. J Dermatol Sci 39. Spritz RA, Strunk K, Giebel LB, King RA: Detection of tyrosinase 3:181-185,1992