Description

Strain Information

Former Names C3H/HeSn-Rab27aash    (Changed: 15-DEC-04 ) Type Coisogenic; Mutant Strain; Spontaneous Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse

Description
Ashen mice have a lightened coat color that is gray on a non-agouti background similar to that of dilute (Myo5a^d) or leaden (ln) mutants. Lane and Womack reported that on an agouti background the yellow pigment is more dilute in ashen mice resulting in a grayer agouti than that found in dilute or leaden mice, but Wu et al. subsequently reported that dilute and ashen mice have identical degrees of coat color dilution. This pigment dilution results from defective trafficking of melanosomes that are normally found throughout the dendrites of melanocytes. Similar to that seen in leaden mutants, ashen melanosomes are clumped around the nucleus and sparse in the dendrites where normally they are released. Melanosome trafficking from the melanocyte cell body to the ends of the dendrites results from a microtubule-based bidirectional transport. MYO5A is essential for retaining the melanosomes in the ends of the dendrites and preventing their retrograde transport back toward the cell body. In ashen mice MYO5A fails to colocalize with melanosomes indicating that RAB27A is required in some way to facilitate this association. (Lane and Womack, 1979; Wu et al., 1998 and 2001.)

Ashen mice have increased bleeding times and their platelets have fewer platelet dense granules and less serotonin than normal. This has not been reported for leaden or dilute mice. Diminished target cell lysis is found using ashen CTLs and NK cells. This is due to diminished granule exocytosis although Fas-Fas ligand mediated CTL cytotoxicity appears to be normal. Polarization of these ashen lytic granules is normal, but they fail to dock at the target membrane. Mice with the dilute mutation have normal CTL activity. (Wilson et al., 2001; Haddad et al., 2001; Stinchcombe et al., 2001.)

Griscelli syndrome in humans is characterized by pigmentary dilution of the skin and hair due to defective melanosome release from melanocytes. This syndrome has been associated with mutations in either RAB27A or MYO5A. In cases with mutations in RAB27A the disease does not have a neurological component, but does include haemophagocytic syndrome, a severe activation of T cells and macrophages. In cases with mutations in MYO5A the disease includes severe neurological impairment but no immunological defects. This variation in disease phenotype is paralleled in mice with mutations in these genes. Thus, certain mutations in Myo5a are models for Griscelli syndrome with neurologic impairment and the ashen mutation (Rab27a^ash) is a model for Griscelli syndrome with hemophagocytic syndrome. (Manasche et al., 2000; Pastural et al., 2000.)

Development
The ashen (Rab27a^ash) mutation arose spontaneously in strain C3H/HeSn at F85 in 1975 at the Jackson Laboratory. The mutation was maintained on the C3H/HeSn background by forced heterozygosis (mating a heterozygote x a homozygote). It was cryopreserved in 1980 by mating heterozygous females with homozygous males to generate embryos. It was removed from the shelf in 1995.

Control Information

	Control
	Heterozygote from the colony
	000661 C3H/HeSnJ
Considerations for Choosing Controls

Related Strains

Strains carrying   Rab27a^ash allele

006936

C3H/HeSn-Rab27aash/JLlp

View Strains carrying   Rab27a^ash     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Storage Pool Platelet Disease - 5

5 Conditionally targeted allele(s)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Rab27a^ash/Rab27a^ash

        C3H/HeDiSn

• pigmentation phenotype
• abnormal Harderian gland pigmentation (MGI Ref ID J:4458)
  • melanocytes have fine dendrites and granules are concentrated around the nucleus;
  • melanocytes of normal siblings are long and granules widely distributed
• abnormal coat color (MGI Ref ID J:4458)
• diluted coat color (MGI Ref ID J:4458)
  • mutants on a nonagouti background are similar to homozygous Myo5a and Mlph mutants
  • mutants with an agouti background, and therefore greater dilution of yellow pigment, have a grayer adult coat than mice with a nonagouti background
• abnormal melanocyte morphology (MGI Ref ID J:4458)
• abnormal melanosome transport (MGI Ref ID J:134370)
• abnormal skin pigmentation (MGI Ref ID J:4458)
  • by 3-4 days of age mutant mice have lighter skin pigmentation than normal siblings
• skin/coat/nails phenotype
• *normal* skin/coat/nails phenotype (MGI Ref ID J:63231)
  • melanocyte dendritic arbors are normal
• abnormal coat color (MGI Ref ID J:4458)
• diluted coat color (MGI Ref ID J:4458)
  • mutants on a nonagouti background are similar to homozygous Myo5a and Mlph mutants
  • mutants with an agouti background, and therefore greater dilution of yellow pigment, have a grayer adult coat than mice with a nonagouti background
• abnormal skin pigmentation (MGI Ref ID J:4458)
  • by 3-4 days of age mutant mice have lighter skin pigmentation than normal siblings
• hematopoietic system phenotype
• abnormal platelet dense granule number (MGI Ref ID J:63231)
  • 1.3 dense granules per platelet versus 8.4 in C3H controls
• decreased platelet serotonin level (MGI Ref ID J:63231)
  • less than 10% of normal
• platelet storage pool deficiency (MGI Ref ID J:63231)
• homeostasis/metabolism phenotype
• decreased platelet serotonin level (MGI Ref ID J:63231)
  • less than 10% of normal
• increased bleeding time (MGI Ref ID J:63231)
  • bleed time is greater than 15 minutes, versus the 1.7 minutes of C3H controls
• platelet storage pool deficiency (MGI Ref ID J:63231)
• vision/eye phenotype
• *normal* vision/eye phenotype (MGI Ref ID J:63231)
  • normal retinas
• immune system phenotype
• *normal* immune system phenotype (MGI Ref ID J:111253)
  • numbers of thymocytes and splenocytes are normal, splenic T cells have a normal CD4/CD8 distribution, splenic T cells proliferate normally in response to CD3/antigen stimulation, the Fas-Fas ligand pathway is intact, cytotoxic T cells can polarize their secretory granules, CTLA4 induction and interferon gamma secretion are normal, and there is normal biogenesis of effector granules in CTLs such that there is a normal level of granzyme A, B, and perforin per CTL
• abnormal NK cell degranulation (MGI Ref ID J:111253)
  • reduced to approximately one tenth normal
• defective cytotoxic T cell cytolysis (MGI Ref ID J:67600)
  • reduced to approximately one tenth normal
• impaired NK cell cytolysis (MGI Ref ID J:111253)
• cellular phenotype
• abnormal vesicle-mediated transport (MGI Ref ID J:134370)
  • black, end-stage melanosomes accumulate in the cell center of melanocytes due to an inability to capture them in the dendrites, and there is rapid, bidirectional, microtubule-dependent movement of the melanosomes between the cell center and periphery

Rab27a^ash/Rab27a^ash

        C3H/HeSn-Rab27a^ash/JRos

• hematopoietic system phenotype
• decreased platelet serotonin level (MGI Ref ID J:137593)
• homeostasis/metabolism phenotype
• decreased platelet serotonin level (MGI Ref ID J:137593)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Rab27a^ash related

Cell Biology Research
Vesicular Trafficking

Dermatology Research
Color and White Spotting Defects

Hematological Research
Clotting Defects
Platelet Defects

Immunology and Inflammation Research
Immunodeficiency Associated with Other Defects

Mouse/Human Gene Homologs
Griscelli Syndrome (with haemophagocytic syndrome)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Rab27aash
Allele Name		ashen
Allele Type		Spontaneous
Common Name(s)		ash;
Strain of Origin		C3H/HeSn
Gene Symbol and Name		Rab27a, RAB27A, member RAS oncogene family
Chromosome		9
Gene Common Name(s)		2210402C08Rik; 2410003M20Rik; 4933437C11Rik; GS2; HsT18676; MGC112618; MGC117246; RAB27; RAM; RIKEN cDNA 2210402C08 gene; RIKEN cDNA 2410003M20 gene; RIKEN cDNA 4933437C11 gene; ash; ashen;
Molecular Note		Sequence analysis of the coding region revealed an A to T transversion in the third base pair of the splice donor site downstream of exon 4. This results in activation of two cryptic downstream splice donor sites and the addition of an intron into the Rab27a message. [MGI Ref ID J:63231]

Genotyping

Genotyping Information

This strain will not have a genotyping protocol or one is not currently available.

Helpful Links

Optimizing PCR Protocols

References

References

Additional References

Hume AN; Collinson LM; Rapak A; Gomes AQ; Hopkins CR; Seabra MC. 2001. Rab27a regulates the peripheral distribution of melanosomes in melanocytes. J Cell Biol 152(4):795-808. [PubMed: 11266470]  [MGI Ref ID J:67601]

Stinchcombe JC; Barral DC; Mules EH; Booth S; Hume AN; Machesky LM; Seabra MC; Griffiths GM. 2001. Rab27a is required for regulated secretion in cytotoxic t lymphocytes. J Cell Biol 152(4):825-34. [PubMed: 11266472]  [MGI Ref ID J:67600]

Wilson SM; Yip R; Swing DA; O'Sullivan TN; Zhang Y; Novak EK; Swank RT; Russell LB; Copeland NG; Jenkins NA. 2000. A mutation in Rab27a causes the vesicle transport defects observed in ashen mice. Proc Natl Acad Sci U S A 97(14):7933-8. [PubMed: 10859366]  [MGI Ref ID J:63231]

Rab27a^ash related

Barral DC; Ramalho JS; Anders R; Hume AN; Knapton HJ; Tolmachova T; Collinson LM; Goulding D; Authi KS; Seabra MC. 2002. Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome. J Clin Invest 110(2):247-57. [PubMed: 12122117]  [MGI Ref ID J:79756]

Chan WT; Sherer NM; Uchil PD; Novak EK; Swank RT; Mothes W. 2008. Murine leukemia virus spreading in mice impaired in the biogenesis of secretory lysosomes and Ca2+-regulated exocytosis. PLoS ONE 3(7):e2713. [PubMed: 18629000]  [MGI Ref ID J:139279]

Chintala S; Tan J; Gautam R; Rusiniak ME; Guo X; Li W; Gahl WA; Huizing M; Spritz RA; Hutton S; Novak EK; Swank RT. 2007. The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules. Blood 109(4):1533-40. [PubMed: 17062724]  [MGI Ref ID J:137593]

Futter CE; Ramalho JS; Jaissle GB; Seeliger MW; Seabra MC. 2004. The role of Rab27a in the regulation of melanosome distribution within retinal pigment epithelial cells. Mol Biol Cell 15(5):2264-75. [PubMed: 14978221]  [MGI Ref ID J:91408]

Haddad EK; Wu X; Hammer JA rd; Henkart PA. 2001. Defective granule exocytosis in Rab27a-deficient lymphocytes from Ashen mice. J Cell Biol 152(4):835-42. [PubMed: 11266473]  [MGI Ref ID J:111253]

Hume AN; Collinson LM; Hopkins CR; Strom M; Barral DC; Bossi G; Griffiths GM; Seabra MC. 2002. The leaden gene product is required with Rab27a to recruit myosin Va to melanosomes in melanocytes. Traffic 3(3):193-202. [PubMed: 11886590]  [MGI Ref ID J:105323]

Jancic C; Savina A; Wasmeier C; Tolmachova T; El-Benna J; Dang PM; Pascolo S; Gougerot-Pocidalo MA; Raposo G; Seabra MC; Amigorena S. 2007. Rab27a regulates phagosomal pH and NADPH oxidase recruitment to dendritic cell phagosomes. Nat Cell Biol 9(4):367-78. [PubMed: 17351642]  [MGI Ref ID J:126381]

Kasai K; Ohara-Imaizumi M; Takahashi N; Mizutani S; Zhao S; Kikuta T; Kasai H; Nagamatsu S; Gomi H; Izumi T. 2005. Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation. J Clin Invest 115(2):388-96. [PubMed: 15690086]  [MGI Ref ID J:95915]

Lane PW; Womack JE. 1979. Ashen, a new color mutation on chromosome 9 of the mouse. J Hered 70:133-135.  [MGI Ref ID J:4458]

Lane PW; Womack JE. 1977. New mutations and enzyme variants Mouse News Lett 57:18.  [MGI Ref ID J:24758]

Langdon WY; Theodore TS; Buckler CE; Stimpfling JH; Martin MA; Morse HC 3d. 1984. Relationship between a retroviral germ line reintegration and a new mutation at the ashen locus in B10.F mice. Retroviral integration and an ashen mutation. Virology 133(1):183-90. [PubMed: 6322428]  [MGI Ref ID J:7366]

Moore KJ; Swing DA; Copeland NG; Jenkins NA. 1990. Interaction of the murine dilute suppressor gene (dsu) with fourteen coat color mutations [published erratum appears in Genetics 1990 Sep;126(1):285] Genetics 125(2):421-30. [PubMed: 2379821]  [MGI Ref ID J:29467]

Moore KJ; Swing DA; Rinchik EM; Mucenski ML; Buchberg AM; Copeland NG; Jenkins NA. 1988. The murine dilute suppressor gene dsu suppresses the coat-color phenotype of three pigment mutations that alter melanocyte morphology, d, ash and ln. Genetics 119(4):933-41. [PubMed: 3410303]  [MGI Ref ID J:9309]

Nguyen T; Wei ML. 2004. Characterization of melanosomes in murine Hermansky-Pudlak syndrome: mechanisms of hypopigmentation. J Invest Dermatol 122(2):452-60. [PubMed: 15009730]  [MGI Ref ID J:88797]

Novak EK; Gautam R; Reddington M; Collinson LM; Copeland NG; Jenkins NA; McGarry MP; Swank RT. 2002. The regulation of platelet-dense granules by Rab27a in the ashen mouse, a model of Hermansky-Pudlak and Griscelli syndromes, is granule-specific and dependent on genetic background. Blood 100(1):128-35. [PubMed: 12070017]  [MGI Ref ID J:77395]

Pachlopnik Schmid J; Ho CH; Diana J; Pivert G; Lehuen A; Geissmann F; Fischer A; de Saint Basile G. 2008. A Griscelli syndrome type 2 murine model of hemophagocytic lymphohistiocytosis (HLH). Eur J Immunol 38(11):3219-25. [PubMed: 18991284]  [MGI Ref ID J:141404]

Silvers WK. 1979. The Coat Colors of Mice; A Model for Mammalian Gene Action and Interaction. In: The Coat Colors of Mice. Springer-Verlag, New York.  [MGI Ref ID J:78801]

Stinchcombe JC; Barral DC; Mules EH; Booth S; Hume AN; Machesky LM; Seabra MC; Griffiths GM. 2001. Rab27a is required for regulated secretion in cytotoxic t lymphocytes. J Cell Biol 152(4):825-34. [PubMed: 11266472]  [MGI Ref ID J:67600]

Tiwari S; Italiano JE Jr; Barral DC; Mules EH; Novak EK; Swank RT; Seabra MC; Shivdasani RA. 2003. A role for Rab27b in NF-E2-dependent pathways of platelet formation. Blood 102(12):3970-9. [PubMed: 12907454]  [MGI Ref ID J:86678]

Tolmachova T; Abrink M; Futter CE; Authi KS; Seabra MC. 2007. Rab27b regulates number and secretion of platelet dense granules. Proc Natl Acad Sci U S A 104(14):5872-7. [PubMed: 17384153]  [MGI Ref ID J:120307]

Tolmachova T; Anders R; Stinchcombe J; Bossi G; Griffiths GM; Huxley C; Seabra MC. 2004. A general role for Rab27a in secretory cells. Mol Biol Cell 15(1):332-44. [PubMed: 14617806]  [MGI Ref ID J:95342]

Wilson SM; Yip R; Swing DA; O'Sullivan TN; Zhang Y; Novak EK; Swank RT; Russell LB; Copeland NG; Jenkins NA. 2000. A mutation in Rab27a causes the vesicle transport defects observed in ashen mice. Proc Natl Acad Sci U S A 97(14):7933-8. [PubMed: 10859366]  [MGI Ref ID J:63231]

Wu X; Rao K; Bowers MB; Copeland NG; Jenkins NA; Hammer JA rd. 2001. Rab27a enables myosin Va-dependent melanosome capture by recruiting the myosin to the organelle. J Cell Sci 114(Pt 6):1091-100. [PubMed: 11228153]  [MGI Ref ID J:134370]

Health & husbandry

Health & Colony Maintenance Information

Currently there no information available for this strain. This may be due to the supply level of this strain.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Mouse Mutant Resource collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Heterozygote from the colony
	000661 C3H/HeSnJ
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

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