A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse.

Giebel, Lutz B.; Tripathi, R. K.; King, Richard A.; Spritz, Richard A.

doi:10.1172/jci115075

Cited by 86 publications

(47 citation statements)

References 19 publications

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“…As ubset of OCA1 relatedm utations, including R402Q, [32] P406L, [33] and R422Q, [34] causes temperature-sensitive oculocutaneous albinism (OCA1-TS), due to at emperature-sensitive form of TYR with optimal tyrosinase activity at temperatures below 37 8C. As aresult,pigmentation is generally more prominent in the extremities (ears, face and legs), where the temperature is lower than in other parts of the body.I nt he TYR model( Figure 6) R402 is surface-exposed and forms ah ydrogen bond with Q399.…”

Section: Analysis Of Oca-related Mutationsmentioning

confidence: 99%

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Lai

Wichers

Soler-López

et al. 2017

Chemistry A European J

195

208

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Melanin is the main pigment responsible for the color of human skin, hair and eye. Its biosynthesis requires three melanogenic enzymes,t yrosinase (TYR), andt he tyrosinase-relatedp roteins TYRP1 and TYRP2. Thed ifficulty of isolating pure and homogeneous proteins from endogenous sources has hampered their study,and resulted in many contradictory findings regarding their physiological functions. In this review,w es ummarize recent advances on the structure and function of TYR and TYRPs by virtue of the crystal structure of human TYRP1, which is the first available structureo f am ammalian melanogenic enzyme. This structure, combined with tyrosinase structures from other lower eukaryotes and mutagenesis studies of key actives ite residues,s heds light on the mechanism of TYR and TYRPs. Furthermore, a TYRP1-based homology model of TYR provides ah igh-quality platform to map and analyze albinism-related mutations, as wella st he design of specific antimelanogenic compounds. Finally,w ep rovide perspectives for future structure/ functionstudies of TYR and TYRPs.

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Section: Analysis Of Oca-related Mutationsmentioning

confidence: 99%

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Lai

Wichers

Soler-López

et al. 2017

Chemistry A European J

195

208

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“…With the exception of the ts-type I oculocutaneous albinism (29), spontaneous ts mutations have rarely been reported in the human. We provide evidence here that ts mutations of the zap70 gene are involved in human SCIDs.…”

Section: Temperature-sensitive Zap70mentioning

confidence: 99%

Temperature-sensitive ZAP70 Mutants Degrading through a Proteasome-independent Pathway

Matsuda¹,

Suzuki-Fujimoto²,

Minowa³

et al. 1999

Journal of Biological Chemistry

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CD8 deficiency is an autosomal recessive form of severe combined immunodeficiency diseases characterized by the absence of CD8؉ T lymphocytes and impaired T cell functions. We identified two novel missense mutations in the zap70 genes of a CD8-deficiency patient. One mutation (P80Q) affects a residue in an SH2 domain and another (M572L) in the kinase subdomain XI. Both mutations cause a degradation of ZAP70 protein in a temperature-sensitive manner through an ATPdependent and proteasome-independent pathway. We further demonstrated that Cdc37, a protein kinase-specific chaperone, bound to M572L but not P80Q mutant and restored the expression of the M572L mutant when overexpressed. The restoration of M572L mutant by Cdc37 required the function of HSP90. These results indicate that Cdc37 in conjunction with HSP90 functions as a molecular chaperone for a temperature-sensitive kinase domain mutant of ZAP70.CD8 deficiency is an autosomal recessive form of severe combined immunodeficiency diseases (SCIDs) 1 and is associated with defects in the ZAP70 protein tyrosine kinase (PTK), which plays a pivotal role in signal transduction through the T cell receptor (TCR) (1-5). Upon TCR stimulation, ZAP70 is recruited to tyrosine-phosphorylated immunoreceptor tyrosinebased activation motifs (ITAMs) within the cytoplasmic domains of TCR subunits; this is an essential step for ZAP70 activation and subsequent cellular signaling pathways (6 -8). Association of ZAP70 with the TCR is mediated by an interaction between the two SH2 domains of the ZAP70 molecule arranged in tandem and the two phosphorylated tyrosine residues in the ITAM (9 -13).All of the mutations in the ZAP70 molecule that have been reported to cause SCID in humans cluster around the kinase subdomain VIII, resulting in instability of the ZAP70 protein (3-5). In general, misfolded proteins are recognized by cellular proteins, chaperones and proteases. Molecular chaperones assist in the proper folding of misfolded polypeptide and render it functional, whereas proteases eliminate such a polypeptide (14). It is thus likely that the counterbalance between chaperones and proteases determines the stability of mutant ZAP70 molecules. With respect to proteases, it is widely accepted that the ubiquitin-proteasome system is involved in degradation of abnormal proteins (15,16). However, the contribution of proteasomes to the instability of mutant ZAP70 proteins is yet to be determined.We show here that two novel mis-sense mutations in the zap70 genes of a CD8-deficiency patient cause degradation of ZAP70 protein in vivo in a temperature-sensitive (ts) manner through an ATP-dependent and proteasome-independent pathway. We also show that overexpression of Cdc37 (17, 18), a protein kinase-specific molecular chaperone, preferentially restores the expression of a kinase-domain mutant of the ZAP70 molecule even at the nonpermissive temperature.

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“…4), although this will depend on the location on the body and whether it is clothed or unclothed. For example, a temperature-sensitive form of tyrosinase has been shown to underlie the variable peripheral pigmentation seen in type 1 oculocutaneous albinism, so that warm areas show lighter pigmentation and cool areas are darker (8,26). It might therefore be interesting to determine whether melanomas show different distributions in kindreds carrying temperature-sensitive mutations versus those with temperature-insensitive lesions.…”

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confidence: 99%

Temperature-Sensitive Mutants of p16^CDKN2 Associated with Familial Melanoma

Parry

Peters

1996

Molecular and Cellular Biology

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Altered expression or function of the p16CDKN2 tumor suppressor gene on chromosome 9p21 occurs in a wide range of human tumors, and mutations in the gene have been shown to segregate with familial predisposition to malignant melanoma. We have used a variety of assays to examine the functional properties of tumorassociated alleles, including eight premature termination mutants, eight missense mutants, and three isoforms of p16 initiated at different amino-terminal methionine codons. The amino-and carboxy-terminal domains of the protein, outside the ankyrin-like repeats, appeared to be dispensable, but the majority of the premature termination mutations led to loss of function. Of the missense mutations tested, four displayed clear loss of function whereas two behaved like the wild type under all conditions tested. The remaining two mutations, a G-to-W mutation at position 101 (G101W) and V126D, both of which are associated with familial melanoma, were found to be temperature sensitive for binding to Cdk4 and Cdk6 in vitro, for inhibiting cyclin D1-Cdk4 in a reconstituted pRb-kinase assay, and for increasing the proportion of G 1 -phase cells following transfection. These findings clarify previous disparities and argue strongly that p16 CDKN2 is a bona fide tumor suppressor associated with familial melanoma.

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A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse.

Cited by 86 publications

References 19 publications

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Temperature-sensitive ZAP70 Mutants Degrading through a Proteasome-independent Pathway

Temperature-Sensitive Mutants of p16^CDKN2 Associated with Familial Melanoma

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A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse.

Cited by 86 publications

References 19 publications

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins

Temperature-sensitive ZAP70 Mutants Degrading through a Proteasome-independent Pathway

Temperature-Sensitive Mutants of p16CDKN2 Associated with Familial Melanoma

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Temperature-Sensitive Mutants of p16^CDKN2 Associated with Familial Melanoma