Melanophilin Explained

Melanophilin is a carrier protein which in humans is encoded by the MLPH gene.^{[1] [2]} Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.

Function

This gene encodes a member of the exophilin subfamily of Rab effector proteins. The protein forms a ternary complex with the small Ras-related GTPase Rab27A in its GTP-bound form and the motor protein myosin Va.^[3] A similar protein complex in mouse functions to tether pigment-producing organelles called melanosomes to the actin cytoskeleton in melanocytes, and is required for visible pigmentation in the hair and skin.^[4]

In melanocytic cells MLPH gene expression may be regulated by MITF.^[5]

Clinical significance

A mutation in this gene results in Griscelli syndrome type 3, which is characterized by a silver-gray hair color and abnormal pigment distribution in the hair shaft.

Mutations in melanophilin cause the "dilute" coat color phenotype in dogs^[6] and cats.^[7] Variation in this gene appears to have been a target for recent natural selection in humans, and it has been hypothesized that this is due to a role in human pigmentation.^[8]

Further reading

• Passeron T, Bahadoran P, Bertolotto C, etal . Cyclic AMP promotes a peripheral distribution of melanosomes and stimulates melanophilin/Slac2-a and actin association . FASEB J. . 18 . 9 . 989–91 . 2004 . 15059972 . 10.1096/fj.03-1240fje . free . 24564755 .
• Fukuda M . Distinct Rab binding specificity of Rim1, Rim2, rabphilin, and Noc2. Identification of a critical determinant of Rab3A/Rab27A recognition by Rim2 . J. Biol. Chem. . 278 . 17 . 15373–80 . 2003 . 12578829 . 10.1074/jbc.M212341200 . free .
• Fukuda M, Kuroda TS . Slac2-c (synaptotagmin-like protein homologue lacking C2 domains-c), a novel linker protein that interacts with Rab27, myosin Va/VIIa, and actin . J. Biol. Chem. . 277 . 45 . 43096–103 . 2002 . 12221080 . 10.1074/jbc.M203862200 . free .
• Westbroek W, Lambert J, Bahadoran P, etal . Interactions of human Myosin Va isoforms, endogenously expressed in human melanocytes, are tightly regulated by the tail domain . J. Invest. Dermatol. . 120 . 3 . 465–75 . 2003 . 12603861 . 10.1046/j.1523-1747.2003.12068.x . free .
• Fukuda M, Kuroda TS . Missense mutations in the globular tail of myosin-Va in dilute mice partially impair binding of Slac2-a/melanophilin . J. Cell Sci. . 117 . Pt 4 . 583–91 . 2004 . 14730011 . 10.1242/jcs.00891 . free .
• Seabra MC, Coudrier E . Rab GTPases and myosin motors in organelle motility . Traffic . 5 . 6 . 393–9 . 2004 . 15117313 . 10.1111/j.1398-9219.2004.00190.x . 46201875 .
• Bahadoran P, Busca R, Chiaverini C, etal . Characterization of the molecular defects in Rab27a, caused by RAB27A missense mutations found in patients with Griscelli syndrome . J. Biol. Chem. . 278 . 13 . 11386–92 . 2003 . 12531900 . 10.1074/jbc.M211996200 . free .
• Wu X, Sakamoto T, Zhang F, etal . In vitro reconstitution of a transport complex containing Rab27a, melanophilin and myosin Va . FEBS Lett. . 580 . 25 . 5863–8 . 2006 . 17045265 . 10.1016/j.febslet.2006.09.047 . 23921179 . free .
• Ménasché G, Ho CH, Sanal O, Feldmann J, Tezcan I, Ersoy F, Houdusse A, Fischer A, de Saint Basile G . Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1) . J. Clin. Invest. . 112 . 3 . 450–6 . August 2003 . 12897212 . 166299 . 10.1172/JCI18264 .
• Gerhard DS, Wagner L, Feingold EA, etal . The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Fukuda M, Kuroda TS, Mikoshiba K . Slac2-a/melanophilin, the missing link between Rab27 and myosin Va: implications of a tripartite protein complex for melanosome transport . J. Biol. Chem. . 277 . 14 . 12432–6 . 2002 . 11856727 . 10.1074/jbc.C200005200 . free .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Lukusa T, Vermeesch JR, Holvoet M, etal . Deletion 2q37.3 and autism: molecular cytogenetic mapping of the candidate region for autistic disorder . Genet. Couns. . 15 . 3 . 293–301 . 2004 . 15517821 .
• Clark HF, Gurney AL, Abaya E, etal . The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment . Genome Res. . 13 . 10 . 2265–70 . 2003 . 12975309 . 10.1101/gr.1293003 . 403697 .
• Fukuda M . Synaptotagmin-like protein (Slp) homology domain 1 of Slac2-a/melanophilin is a critical determinant of GTP-dependent specific binding to Rab27A . J. Biol. Chem. . 277 . 42 . 40118–24 . 2002 . 12189142 . 10.1074/jbc.M205765200 . free .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2002 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Park JW, Cai J, McIntosh I, etal . High throughput SNP and expression analyses of candidate genes for non-syndromic oral clefts . J. Med. Genet. . 43 . 7 . 598–608 . 2006 . 16415175 . 10.1136/jmg.2005.040162 . 2564555 .

Notes and References

1. Matesic LE, Yip R, Reuss AE, Swing DA, O'Sullivan TN, Fletcher CF, Copeland NG, Jenkins NA . Mutations in Mlph, encoding a member of the Rab effector family, cause the melanosome transport defects observed in leaden mice . Proc. Natl. Acad. Sci. U.S.A. . 98 . 18 . 10238–43 . August 2001 . 11504925 . 56945 . 10.1073/pnas.181336698 . 2001PNAS...9810238M . free .
2. Strom M, Hume AN, Tarafder AK, Barkagianni E, Seabra MC . A family of Rab27-binding proteins. Melanophilin links Rab27a and myosin Va function in melanosome transport . J. Biol. Chem. . 277 . 28 . 25423–30 . July 2002 . 11980908 . 10.1074/jbc.M202574200 . free .
3. Nagashima K, Torii S, Yi Z, Igarashi M, Okamoto K, Takeuchi T, Izumi T . Melanophilin directly links Rab27a and myosin Va through its distinct coiled-coil regions . FEBS Lett. . 517 . 1–3 . 233–8 . April 2002 . 12062444 . 10.1016/S0014-5793(02)02634-0 . 14844547 . free .
4. Web site: Entrez Gene: MLPH Melanophilin .
5. Hoek KS, Schlegel NC, Eichhoff OM, etal . Novel MITF targets identified using a two-step DNA microarray strategy . Pigment Cell Melanoma Res. . 21 . 6 . 665–76 . 2008 . 19067971 . 10.1111/j.1755-148X.2008.00505.x . 24698373 . free .
6. Drögemüller C, Philipp U, Haase B, Günzel-Apel AR, Leeb T . A noncoding melanophilin gene (MLPH) SNP at the splice donor of exon 1 represents a candidate causal mutation for coat color dilution in dogs . J. Hered. . 98 . 5 . 468–73 . 2007 . 17519392 . 10.1093/jhered/esm021 . free .
7. Ishida Y, David VA, Eizirik E, Schäffer AA, Neelam BA, Roelke ME, Hannah SS, O'brien SJ, Menotti-Raymond M . A homozygous single-base deletion in MLPH causes the dilute coat color phenotype in the domestic cat . Genomics . 88 . 6 . 698–705 . December 2006 . 16860533 . 10.1016/j.ygeno.2006.06.006 .
8. Pickrell JK, Coop G, Novembre J, Kudaravalli S, Li JZ, Absher D, Srinivasan BS, Barsh GS, Myers RM, Feldman MW, Pritchard JK . Jonathan K. Pritchard . Signals of recent positive selection in a worldwide sample of human populations . Genome Res. . 19 . 5 . 826–37 . May 2009 . 19307593 . 2675971 . 10.1101/gr.087577.108 .