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Type Mutant Strain; Spontaneous Mutation; Species laboratory mouse H2 Haplotype b Appearance
black coat with light patches, curly vibrissae
Related Genotype: a/a Atp7aMo-br/+
black
Related Genotype: a/a +/Y or a/a +/+Description
Heterozygous females carrying the brindled allele (Atp7aMo-br) are very similar to mottled heterozygous females (Atp7aMo/+) in appearance but have normal viability. They have curly vibrissae, but the coat is not noticeably waved. Hemizygous males are almost devoid of pigment except in the eyes and ears. The vibrissae are strongly curled, and the coat is wavy. Males usually die by two weeks of age, but a few have lived and been fertile. They have a behavioral abnormality consisting of a slight tremor, uncoordinated gait, and clasping of the hindfeet when held up by the tail. Histological examination of the brain of brindled males shows widespread neuronal degeneration in the cerebral cortex and thalamic nuclei and scattered degeneration in the cerebellum. Heterozygous females have been shown to have neurochemical abnormalities as well. In contrast to mice bearing other Atp7a alleles, brindled mice have no aortic lesions and no defect in crosslinking of collagen and elastin. Brindled males have defective placental transport and defective intestinal absorption of copper. Parenteral injection of copper at 7 to 10 days of age prevents tremor and early death, allows normal pigmentation, improves growth, produces normal concentrations of copper in organs previously deficient (except liver), producesnormal activity of some copper-dependent enzymes, and prevents neuronal degeneration.Development
Brindled (Atp7aMo-br) arose spontaneously in the C57BL strain about 1953 (Fraser, A.S. et al. 1953. J Genetics 51:217-221). It was imported into the Jackson Laboratory on the C57BL/6J background in 1995 from Christine Peterson at The Andrus Gerontology Center of the University of Southern California. Female heterozygotes were bred to C57BL/6J and their female heterozygous offspring were again backcrossed to C57BL/6J before hysterectomy rederivation. This strain is maintained by mating a heterozygous brindled female to a C57BL/6J male each generation. In 2000 this strain reached generation +N11 and in 2006 it reached generation +N25.
| Control | ||
|---|---|---|
| Wild-type from the colony | ||
| 000664 C57BL/6J | ||
| Considerations for Choosing Controls | ||
Strains carrying other alleles of Atp7a
000535 B6.Cg-Atp7aMo-blo/J 001381 B6.Cg-Atp7aMo-pew2J/J 000053 B6.Cg-Atp7aMo-to/J 002062 B6C3Fe a/a-Atp7aMo-8J/J 002044 B6Ei.Cg-Atp7aMo-blo/J 000813 CBA/J-Atp7aMo-pew/J 000623 TR/DiEiJ View Strains carrying other alleles of Atp7a (7 strains)
Related Disease (OMIM) Terms
Menkes Disease Mammalian Phenotype Terms assigned by genotype
Atp7aMo-br/Y
C57BL/6-Atp7aMo-br/J
- homeostasis/metabolism phenotype
- abnormal enzyme/coenzyme activity (MGI Ref ID J:105736)
- specific activity of superoxide dismutase 3 (SOD3) in fibroblasts is markedly reduced compared to wild-type cells
The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.
Atp7aMo-br/Y
involves: C57BL
- homeostasis/metabolism phenotype
- abnormal copper level (MGI Ref ID J:5462)
- 7-10 day-old males show an accumulation of copper in the intestinal wall; copper levels in brain are reduced by 40%
- abnormal liver copper level (MGI Ref ID J:5462)
- 7-10 day-old males have significantly reduced (by >2-fold) liver copper levels
- decreased circulating copper level (MGI Ref ID J:5462)
- significant reduction in serum copper (mostly found in ceruplasmin) in males is observed
- abnormal noradrenaline level (MGI Ref ID J:5462)
- brain levels are reduced by 66% compared to wild-type males
- liver/biliary system phenotype
- abnormal liver copper level (MGI Ref ID J:5462)
- 7-10 day-old males have significantly reduced (by >2-fold) liver copper levels
Research Applications
This mouse can be used to support research in many areas including:Atp7aMo-br related
Dermatology Research
Color and White Spotting Defects
Developmental Biology Research
Defects in Extracellular Matrix Molecules
Metabolism Research
Mouse/Human Gene Homologs
Menkes syndrome
Neurobiology Research
Metabolic Defects
| Allele Symbol | Atp7aMo-br | ||
|---|---|---|---|
| Allele Name | brindled | ||
| Common Name(s) | Br; Mobr; | ||
| Strain of Origin | C57BL | ||
| Gene Symbol and Name | Atp7a, ATPase, Cu++ transporting, alpha polypeptide | ||
| Chromosome | X | ||
| Gene Common Name(s) | Blo; FLJ17790; MK; MNK; Menkes protein; Mo; blotchy; br; mottled; | ||
| General Note | Atp7aMo-br, brindled, semidominant. The brindled allele arose spontaneously in the C57BL inbred strain (J:13041). Heterozygous females are very similar to Atp7aMo/+ females in appearance but have normal viability. They have curly vibrissae, but the coat is not noticeably waved. Hemizygous males are almost devoid of pigment except in the eyes and ears. The vibrissae are strongly curled, and the coat is wavy. The abnormalities of hair structure have been described by Gr\"uneberg (J:5137).Males usually die when 2 weeks old, but a few have lived and been fertile. They have a behavioral abnormality consisting of a slight tremor, uncoordinated gait, and clasping of the hindfeet when held up by the tail (J:249, J:164). Females homozygousfor Atp7aMo-br, and also heterozygous Atp7aMo-br/Atp7aMo and Atp7aMo-br/Atp7aMo-to females are identical in phenotype to hemizygous Atp7aMo-br males and die at the same age (J:164, J:12963).Histological examination of the brain of brindled males shows widespread neuronal degeneration in the cerebral cortex and thalamic nuclei and scattered degeneration in the cerebellum (J:6113). Heterozygous females have been shown to have neurochemicalabnormalities as well (J:2026). In contrast to mice bearing other Atp7a alleles, brindled mice have no aortic lesions (J:12963) and no defect in crosslinking of collagen and elastin. Brindled males do, however, have a 30 to 40% reduction in lysyl oxidaseactivity in skin (J:5777). They have reduced synthesis of noradrenalin by dopamine-ß-hydroxylase in the brain and peripheral nervous system (J:5323), and decreased activity of cytochrome C oxidase and superoxide dismutase (J:5830). These enzymes are all copper-dependent or copper-containing, and their reduced activity may be due to defective copper transport in cells of all affected tissues (J:5956, J:617, J:5747, J:12937).Brindled males have defective placental transport and defective intestinal absorption of copper. Copper concentration is high in gut mucosa, kidney, and testis and low in liver, brain, plasma, and most other organs (J:6204, J:6206). Concentration of the copper-binding protein metallothionein in various tissues is correlated with the concentration of copper (J:7370); however, hepatic metallothionein is inducible at normal levels in mutant neonates (J:24041). Parenteral injection of copper at 7 to 10 days of age has a striking therapeutic effect; it prevents tremor and early death, allows normal pigmentation, improves growth, produces normal concentrations of copper in organs previously deficient (except liver), produces normal activity of some copper-dependent enzymes (J:6205, J:7521), and prevents neuronal degeneration (J:6544). In heterozygotes with tabby (Eda), Atp7aMo-br resembles Atp7aMo-blo, and thus appears to act on coat color through an effect in hair follicles (J:5238).Brindled is the closest of the mouse mottled mutations to Menkes disease in phenotype, but no chromosomal abnormality was detected in mice expressing Atp7aMo-br, suggesting a point mutation or very small deletion (J:17493). A 6 bp deletion has in fact been found in the brindled mutant gene (J:38978). | ||
| Molecular Note | Two significant nucleotide changes were noted in the brindled mouse. A 6 bp in frame deletion in exon 11 removed a leucine and an alanine at positions 799 and 800 from the encoded protein. A G-to-A transition mutation was also detected at codon 514 that altered a threonine to alanine, but this alteration is in a region unlikely to affect function. The deletion is in a region postulated to affect Cu transport activity. Western blot analysis demonstrated that a normal sized protein was made from this allele at levels comparable to wild-type. [MGI Ref ID J:38978] [MGI Ref ID J:41388] | ||
This strain will not have a genotyping protocol or one is not currently available.
Helpful Links
Optimizing PCR Protocols
Evans GW; Reis BL. 1978. Impaired copper homeostasis in neonatal male and adult female Brindled (Mobr) mice. J Nutr 108(4):554-60. [PubMed: 564942] [MGI Ref ID J:5956]
Kiaei M; Bush AI; Morrison BM; Morrison JH; Cherny RA; Volitakis I; Beal MF; Gordon JW. 2004. Genetically decreased spinal cord copper concentration prolongs life in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 24(36):7945-50. [PubMed: 15356208] [MGI Ref ID J:92633]
Martin PM; Irino M; Suzuki K; Lewis MH; Mailman RB. 1991. The female brindled mouse as a model of Menkes' disease: the relationship of fur pattern to behavioral and neurochemical abnormalities. Dev Neurosci 13(3):121-9. [PubMed: 1752214] [MGI Ref ID J:2026]
Atp7aMo-br related
Camakaris J; Mann JR; Danks DM. 1979. Copper metabolism in mottled mouse mutants: copper concentrations in tissues during development. Biochem J 180(3):597-604. [PubMed: 573617] [MGI Ref ID J:6204]El Meskini R; Crabtree KL; Cline LB; Mains RE; Eipper BA; Ronnett GV. 2007. ATP7A (Menkes protein) functions in axonal targeting and synaptogenesis. Mol Cell Neurosci 34(3):409-21. [PubMed: 17215139] [MGI Ref ID J:123238]
Evans GW; Reis BL. 1978. Impaired copper homeostasis in neonatal male and adult female Brindled (Mobr) mice. J Nutr 108(4):554-60. [PubMed: 564942] [MGI Ref ID J:5956]
FALCONER DS. 1953. [Total sex-linkage in the house mouse.] Z Indukt Abstamm Vererbungsl 85(2):210-9. [PubMed: 13103353] [MGI Ref ID J:249]
Falconer DS. 1956. Viable and fertile Brindled male, and new evidence for the allelism of the sex-linked genes, Brindled and Mottled Mouse News Lett 15:24-25. [MGI Ref ID J:164]
Falconer DS; Isaacson. 1972. Harlequin and brindled - linkage, and difference between coupling and repulsion phenotypes Mouse News Lett 47:28. [MGI Ref ID J:13531]
Falconer DS; Isaacson JH. 1972. Sex-linked variegation modified by selection in brindled mice. Genet Res 20(3):291-316. [PubMed: 4670054] [MGI Ref ID J:5430]
Fraser A; Sobey S. 1953. Mottled, a sex-modified lethal in the house mouse. J Genet 51:217-221. [MGI Ref ID J:13041]
Grahn D; Fry RJM; Hamilton KF. 1969. Genetic and pathological analysis of the sex-linked allelic series, mottled, in the mouse. Genetics 61:s22-s23. [MGI Ref ID J:12963]
Grimes A; Hearn CJ; Lockhart P; Newgreen DF; Mercer JF. 1997. Molecular basis of the brindled mouse mutant (Mo(br)): a murine model of Menkes disease. Hum Mol Genet 6(7):1037-42. [PubMed: 9215672] [MGI Ref ID J:41388]
Gruneberg H. 1969. Threshold phenomena versus cell heredity in the manifestation of sex-linked genes in mammals. J Embryol Exp Morphol 22(2):145-79. [PubMed: 5361553] [MGI Ref ID J:5137]
Hunt DM. 1976. A study of copper treatment and tissue copper levels in the murine congenital copper deficiency, mottled. Life Sci 19(12):1913-9. [PubMed: 187892] [MGI Ref ID J:5747]
Hunt DM. 1977. Catecholamine biosynthesis and the activity of a number of copper-dependent enzymes in the copper deficient mottled mouse mutants. Comp Biochem Physiol C 57(1):79-83. [PubMed: 17511] [MGI Ref ID J:5830]
Hunt DM. 1974. Primary defect in copper transport underlies mottled mutants in the mouse. Nature 249(460):852-4. [PubMed: 4858102] [MGI Ref ID J:5462]
Hunt DM; Clarke R. 1983. Metallothionein and the development of the mottled disorder in the mouse. Biochem Genet 21(11-12):1175-94. [PubMed: 6670991] [MGI Ref ID J:7370]
Hunt DM; Johnson DR. 1972. An inherited deficiency in noradrenaline biosynthesis in the brindled mouse. J Neurochem 19(12):2811-9. [PubMed: 4405722] [MGI Ref ID J:5323]
Hunt DM; Johnson DR. 1972. Aromatic amino acid metabolism in brindled (Mobr) and viable-brindled (Movbr), two alleles at the mottled locus in the mouse. Biochem Genet 6(1):31-40. [PubMed: 4147174] [MGI Ref ID J:5373]
Kiel-Metzger K; Erickson RP. 1984. Regional localization of sex-specific Bkm-related sequences on proximal chromosome 17 of mice. Nature 310(5978):579-81. [PubMed: 6462245] [MGI Ref ID J:7521]
Kodama H; Meguro Y; Abe T; Rayner MH; Suzuki KT; Kobayashi S; Nishimura M. 1991. Genetic expression of Menkes disease in cultured astrocytes of the macular mouse. J Inherit Metab Dis 14(6):896-901. [PubMed: 1779648] [MGI Ref ID J:617]
Kuznetsov AV; Clark JF; Winkler K; Kunz WS. 1996. Increase of flux control of cytochrome c oxidase in copper-deficient mottled brindled mice. J Biol Chem 271(1):283-8. [PubMed: 8550574] [MGI Ref ID J:30532]
La Fontaine S; Firth SD; Lockhart PJ; Brooks H; Camakaris J; Mercer JF. 1999. Intracellular localization and loss of copper responsiveness of Mnk, the murine homologue of the Menkes protein, in cells from blotchy (Mo blo) and brindled (Mo br) mouse mutants. Hum Mol Genet 8(6):1069-75. [PubMed: 10332039] [MGI Ref ID J:55409]
Llanos RM; Ke BX; Wright M; Deal Y; Monty F; Kramer DR; Mercer JF. 2006. Correction of a mouse model of Menkes disease by the human Menkes gene. Biochim Biophys Acta 1762(4):485-93. [PubMed: 16488577] [MGI Ref ID J:110217]
Lyon MF. 1970. Genetic activity of sex chromosomes in somatic cells of mammals. Philos Trans R Soc Lond B Biol Sci 259(828):41-52. [PubMed: 4399067] [MGI Ref ID J:5238]
Mann JR; Camakaris J; Danks DM. 1979. Copper metabolism in mottled mouse mutants: distribution of 64Cu in brindled (Mobr) mice. Biochem J 180(3):613-9. [PubMed: 573619] [MGI Ref ID J:6206]
Mann JR; Camakaris J; Danks DM; Walliczek EG. 1979. Copper metabolism in mottled mouse mutants: copper therapy of brindled (Mobr) mice. Biochem J 180(3):605-12. [PubMed: 573618] [MGI Ref ID J:6205]
Mann JR; Camakaris J; Francis N; Danks DM. 1981. Copper metabolism in mottled mouse (Mus musculus) mutants. Studies of blotchy (Moblo) mice and a comparison with brindled (Mobr) mice. Biochem J 196(1):81-8. [PubMed: 7197928] [MGI Ref ID J:82681]
Martin P; Ohno M; Southerland SB; Mailman RB; Suzuki K. 1994. Heterotypic sprouting of serotonergic forebrain fibers in the brindled mottled mutant mouse. Brain Res Dev Brain Res 77(2):215-25. [PubMed: 8174230] [MGI Ref ID J:16943]
Martin PM; Irino M; Suzuki K; Lewis MH; Mailman RB. 1991. The female brindled mouse as a model of Menkes' disease: the relationship of fur pattern to behavioral and neurochemical abnormalities. Dev Neurosci 13(3):121-9. [PubMed: 1752214] [MGI Ref ID J:2026]
Mercer JF; Grimes A; Ambrosini L; Lockhart P; Paynter JA; Dierick H; Glover TW. 1994. Mutations in the murine homologue of the Menkes gene in dappled and blotchy mice [see comments] Nat Genet 6(4):374-8. [PubMed: 8054977] [MGI Ref ID J:17493]
Nagara H; Yajima K; Suzuki K. 1981. The effect of copper supplementation on the brindled mouse: a clinico-pathological study. J Neuropathol Exp Neurol 40(4):428-46. [PubMed: 7195926] [MGI Ref ID J:6544]
Niciu MJ; Ma XM; El Meskini R; Pachter JS; Mains RE; Eipper BA. 2007. Altered ATP7A expression and other compensatory responses in a murine model of Menkes disease. Neurobiol Dis 27(3):278-91. [PubMed: 17588765] [MGI Ref ID J:134920]
Paynter JA; Grimes A; Lockhart P; Mercer JF. 1994. Expression of the Menkes gene homologue in mouse tissues lack of effect of copper on the mRNA levels. FEBS Lett 351(2):186-90. [PubMed: 8082762] [MGI Ref ID J:20585]
Piletz JE; Herschman HR. 1983. Hepatic metallothionein synthesis in neonatal Mottled-Brindled mutant mice. Biochem Genet 21(5-6):465-75. [PubMed: 6870774] [MGI Ref ID J:24041]
Prins HW; Van den Hamer CJ. 1979. Primary biochemical defect in copper metabolism in mice with a recessive X-linked mutation analogous to Menkes' disease in man. J Inorg Biochem 10(1):19-27. [PubMed: 571898] [MGI Ref ID J:6150]
Qin Z; Itoh S; Jeney V; Ushio-Fukai M; Fukai T. 2006. Essential role for the Menkes ATPase in activation of extracellular superoxide dismutase: implication for vascular oxidative stress. FASEB J 20(2):334-6. [PubMed: 16371425] [MGI Ref ID J:105736]
Reed V; Boyd Y. 1997. Mutation analysis provides additional proof that mottled is the mouse homologue of Menkes' disease. Hum Mol Genet 6(3):417-23. [PubMed: 9147645] [MGI Ref ID J:38978]
Rossi L; De Martino A; Marchese E; Piccirilli S; Rotilio G; Ciriolo MR. 2001. Neurodegeneration in the animal model of Menkes' disease involves Bcl-2-linked apoptosis. Neuroscience 103(1):181-8. [PubMed: 11311799] [MGI Ref ID J:126025]
Rowe DW; McGoodwin EB; Martin GR; Grahn D. 1977. Decreased lysyl oxidase activity in the aneurysm-prone, mottled mouse. J Biol Chem 252(3):939-42. [PubMed: 14140] [MGI Ref ID J:5777]
Rowe DW; McGoodwin EB; Martin GR; Sussman MD; Grahn D; Faris B; Franzblau C. 1974. A sex-linked defect in the cross-linking of collagen and elastin associated with the mottled locus in mice. J Exp Med 139(1):180-92. [PubMed: 4808708] [MGI Ref ID J:5397]
Sayed AK; Edwards JA; Bannerman RM. 1978. <64>Cu uptake by cultured fibroblasts from Mo<br>/Y mice. Fed Proc 37:746. [MGI Ref ID J:12937]
Schlief ML; Craig AM; Gitlin JD. 2005. NMDA receptor activation mediates copper homeostasis in hippocampal neurons. J Neurosci 25(1):239-46. [PubMed: 15634787] [MGI Ref ID J:97021]
Schlief ML; West T; Craig AM; Holtzman DM; Gitlin JD. 2006. Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity. Proc Natl Acad Sci U S A 103(40):14919-24. [PubMed: 17003121] [MGI Ref ID J:114528]
Schofield AE; Martin PG; Spillett D; Tanner MJ. 1994. The structure of the human red blood cell anion exchanger (EPB3, AE1, band 3) gene. Blood 84(6):2000-12. [PubMed: 8081002] [MGI Ref ID J:20401]
Sundberg JP (ed.). 1994. . In: Handbook of Mouse Mutations with Skin and Hair Abnormalities: Animal Models and Biomedical Tools. CRC Press, Boca Raton. [MGI Ref ID J:30359]
Wenk G; Suzuki K. 1983. Congenital copper deficiency: copper therapy and dopamine-beta-hydroxylase activity in the mottled (brindled) mouse. J Neurochem 41(6):1648-52. [PubMed: 6644305] [MGI Ref ID J:7251]
Yajima K; Suzuki K. 1979. Neuronal degeneration in the brain of the brindled mouse--a light microscope study. J Neuropathol Exp Neurol 38(1):35-46. [PubMed: 571007] [MGI Ref ID J:6113]
Yoshimura N. 1994. Histochemical localization of copper in various organs of brindled mice. Pathol Int 44(1):14-9. [PubMed: 8025644] [MGI Ref ID J:19860]
Yoshimura N; Kida K; Usutani S; Nishimura M. 1995. Histochemical localization of copper in various organs of brindled mice after copper therapy. Pathol Int 45(1):10-8. [PubMed: 7704239] [MGI Ref ID J:23042]
Colony Maintenance
Breeding & Husbandry As hemizygous (Atp7aMo-br/Y) males and homozygous (Atp7aMo-br/Atp7aMo-br)females do not survive to breeding age, this strain must be maintained by breeding heterozygous (Atp7aMo-br/+) females to wild-type males.
*Price(s) in US dollars ($)
Weeks of Age Price* Gender Cryorecovery Fee $1900.00
| Standard Supply | Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information. |
|---|---|
| Supply Notes |
|
*Price(s) in US dollars ($)
Weeks of Age Price* Gender Cryorecovery Fee $2470.00
| Standard Supply | Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information. |
|---|---|
| Supply Notes |
|
| Control | ||
|---|---|---|
| Wild-type from the colony | ||
| 000664 C57BL/6J | ||
| 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. | ||
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