Mutation of melanosome protein RAB38 in
            <i>chocolate</i>
            mice

Loftus, Stacie K.; Larson, Denise M.; Baxter, Laura L.; Antonellis, Anthony; Chen, Yidong; Wu, Xufeng; Jiang, Yuan; Bittner, Michael; Hammer, John A.; Pavan, William J.

doi:10.1073/pnas.072087599

Cited by 156 publications

(183 citation statements)

References 40 publications

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“…Of the two examples visualized as median-joining networks, the RAB38 gene is expressed in melanocytes, and its disruption in mice causes oculocutaneous albinism, lung disease, and platelet deficiency. [29][30][31] This makes RAB38 an interesting novel candidate locus for human pigmentation. The PPP2R2B gene regulates neuronal apoptosis and may affect adenovirus replication.…”

Section: Discussionmentioning

confidence: 99%

Genomic landscape of positive natural selection in Northern European populations

et al. 2009

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Analyzing genetic variation of human populations for detecting loci that have been affected by positive natural selection is important for understanding adaptive history and phenotypic variation in humans. In this study, we analyzed recent positive selection in Northern Europe from genome-wide data sets of 250 000 and 500 000 single-nucleotide polymorphisms (SNPs) in a total of 999 individuals from Great Britain, Northern Germany, Eastern and Western Finland, and Sweden. Coalescent simulations were used for demonstrating that the integrated haplotype score (iHS) and long-range haplotype (LRH) statistics have sufficient power in genome-wide data sets of different sample sizes and SNP densities. Furthermore, the behavior of the F ST statistic in closely related populations was characterized by allele frequency simulations. In the analysis of the North European data set, 60 regions in the genome showed strong signs of recent positive selection. Out of these, 21 regions have not been discovered in previous scans, and many contain genes with interesting functions (eg, RAB38, INFG, NOS1AP, and APOE). In the putatively selected regions, we observed a statistically significant overrepresentation of genetic association with complex disease, which emphasizes the importance of the analysis of positive selection in understanding the evolution of human disease. Altogether, this study demonstrates the potential of genome-wide data sets to discover loci that lie behind evolutionary adaptation in different human populations.

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Section: Discussionmentioning

confidence: 99%

Genomic landscape of positive natural selection in Northern European populations

et al. 2009

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“…The diluted coat color of another mouse mutant, chocolate, has recently been shown to be caused by dysfunctions of Rab38, and targeting of tyrosinase-related protein 1 (Tyrp1) to melanosomes is impaired in chocolate melanocytes (Loftus et al, 2002). Rab38 is also involved in the trafficking of another melanogenic enzyme, tyrosinase, to melanosomes in skin melanocytes (Wasmeier et al, 2006) and to immature melanosomes in retinal pigment epithelial cells (Lopes et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Varp Is a Novel Rab32/38-binding Protein That Regulates Tyrp1 Trafficking in Melanocytes

Tamura

Ohbayashi

Maruta

et al. 2009

MBoC

182

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Two small GTPase Rabs, Rab32 and Rab38, have recently been proposed to regulate trafficking of melanogenic enzymes to melanosomes in mammalian epidermal melanocytes; however, the exact molecular mechanism of Rab32/38-mediated transport of melanogenic enzymes has never been clarified, because no Rab32/38-specific effector has ever been identified. In this study, we screened for a Rab32/38-specific effector by a yeast two-hybrid assay using a guanosine triphosphate (GTP)-locked Rab32/38 as bait and found that VPS9-ankyrin-repeat protein (Varp)/Ankrd27, characterized previously as a guanine nucleotide exchange factor (GEF) for Rab21, functions as a specific Rab32/38-binding protein in mouse melanocyte cell line melan-a. Deletion analysis showed that the first ankyrin-repeat (ANKR1) domain functions as a GTP-dependent Rab32/38-binding domain, but that the N-terminal VPS9 domain (i.e., Rab21-GEF domain) does not. Small interfering RNA-mediated knockdown of endogenous Varp in melan-a cells caused a dramatic reduction in Tyrp1 (tyrosinase-related protein 1) signals from melanosomes but did not cause any reduction in Pmel17 signals. Furthermore, expression of the ANKR1 domain in melan-a cells also caused a dramatic reduction of Tyrp1 signals, whereas the VPS9 domain had no effect. Based on these findings, we propose that Varp functions as the Rab32/38 effector that controls trafficking of Tyrp1 in melanocytes.

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“…For example, we can determine whether ectopic expression of Mitf in Sox10 -/-neural crest cells could rescue all or any of the melanocytic defects. This system is also useful for evaluating biological functions in neural crest development of newly cloned genes obtained from animal mutants or expression arrays (Loftus et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Tail biopsies were taken from the pups for screening of founders by PCR. Wholemount in situ hybridization procedures was performed as described previously (Loftus et al, 2002). Antisense Pax3 probe was made from XhoI linearized plasmid pc3-2 mprd (Goulding et al, 1991) that contains a 2.3-kb Pax3 cDNA insert, using T7 RNA polymerase.…”

Section: Pax3 Promoter Transgenic Micementioning

confidence: 99%

Complementation of melanocyte development in SOX10 mutant neural crest using lineage‐directed gene transfer

Hou

Loftus

Incao

et al. 2003

Developmental Dynamics

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An in vitro gene complementation approach has been developed to dissect gene function and regulation in neural crest (NC) development and disease. The approach uses the avian RCAS virus to express genes in NC cells derived from transgenic mice expressing the RCAS receptor TVA, under the control of defined promoter elements. Constructs for creating TVA transgenic mice were developed using site-specific recombination GATEWAY (GW), compatible vectors that can also be used to facilitate analysis of genomic fragments for transcriptional regulatory elements. By using these GW vectors to facilitate cloning, transgenic mouse lines were generated that express TVA in SOX10-expressing NC stem cells under the control of the Pax3 promoter. The Pax3-tv-a transgene was bred onto a Sox10-deficient background, and the feasibility of complementing genetic NC defects was demonstrated by infecting the Pax3-tv-a cells with an RCAS-Sox10 expression virus, thereby rescuing melanocyte development of Sox10-deficient NC cells. This system will be useful for assessing genetic hierarchies in NC development. Developmental Dynamics 229:54 -62, 2004.

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Mutation of melanosome protein RAB38 in chocolate mice

Cited by 156 publications

References 40 publications

Genomic landscape of positive natural selection in Northern European populations

Genomic landscape of positive natural selection in Northern European populations

Varp Is a Novel Rab32/38-binding Protein That Regulates Tyrp1 Trafficking in Melanocytes

Complementation of melanocyte development in SOX10 mutant neural crest using lineage‐directed gene transfer

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