Strain Name:
B6J.Cg(129S1)-Dp(19Rln1-Gldc)1Uru/UruMmmh
Stock Number:
068238-MU
Citation ID:
RRID:MMRRC_068238-MU
Other Names:
9p24.1 duplication mice; B6.Cg(129S1)-Dup(19Rln1-Gldc)1Uru

Strain Information

Dp(19Rln1-Gldc)1Uru
Name: duplication, Chr 19, Uwe Rudolph 1
Type: Allele
Species: Mus musculus (mouse)
Chromosome: 19
Gldc
Name: glycine decarboxylase
Synonyms: D030049L12Rik, b2b2679Clo, D19Wsu57e
Type: Gene
Species: Mouse
Chromosome: 19
NCBI: 104174
VEGA: 19
HGNC: HGNC:4313
Homologene: 141
Rln1
Name: relaxin 1
Synonyms: rlx
Type: Gene
Species: Mouse
Chromosome: 19
NCBI: 19773
Homologene: 55524
Genetic Alterations
Combination of two gene targetings to generate two loxP sites followed by trans-allelic recombination in vivo to generate the genomic 0.9-Mb duplication.

For the 9p24.1 deletion (MMRRC:68237) and duplication (MMRRC:68238), the deleted or duplicated genes are:

  • Rln1 (relaxin 1),
  • Plgrkt (plasminogen receptor with a C-terminal lysine),
  • Cd274 (CD274 molecule),
  • Pdcd1lg2 (programmed cell death 1 ligand 2),
  • Ric1 (Ric1 homolog, RAB6A GEF complex partner 1),
  • Ermp1 (endoplasmic reticulum metallopeptidase 1),
  • Mlana (Melan-A),
  • 9930021J03Rik (RIKEN cDNA 9930021J03 gene),
  • Ranbp6 (Ran-binding protein 6),
  • Il33 (interleukin 33),
  • Trpd52l3 (tumor protein D52-like 3),
  • Uhrf2 (ubiquitin like with PHD and ring finger domains 2), and
  • Gldc (glycine decarboxylase).
ES Cell Line
v6.5 derived from (C57BL/6 x 129S4/SvJae)F1
Phenotype
9p24.1 copy number variation (CNV) mice are modeled after patients with bipolar disorder with psychotic features and schizoaffective disorder that have been studied extensively and described in the literature (PMID:28216146, 31279534, 29696747). These patients have been found to carry extra copies of these genes on a small supernumerary marker chromosome. These patients have 4 functional copies of the Gldc gene and 3 functional copies of the 9p24.1 gene listed above. We found that the mice display a reduced density of dendritic spines, prepulse inhibition deficits, startle habituation deficits, latent inhibition deficits increased trace fear conditioning and contextual fear conditioning, learning and memory deficits in a water T maze and a Y maze. As glycine augmentation (i.e., the addition of glycine to the antipsychotic clozapine) improved symptoms in the patients significantly, the increased copy number of the glycine decarboxylase gene (Gldc) is very likely responsible for the observed phenotypes. In the brain, it is expressed almost exclusively in astrocytes. Glycine decarboxylase is the rate-limiting enzyme of the glycine cleavage system and degrades glycine, which is a co-agonist at the NMDA receptor. NMDA receptor hypofunction has been hypothesized to be an important event in the pathophysiology of schizophrenia. Thus, we have a very rare case where the increased copy number plays a very important role in the pathophysiology of psychotic disorders. Both expression and activity of GLDC in these mice are increased. Electrophysiological studies are going on to characterize the effect of increased Gldc copy number at the cellular level. We have also performed RNA sequencing in the hippocampus and prefrontal cortex.

Added from donor correspondence:
Donor Note: ... Bodkin and colleagues provided two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype (increased copies of the GLDC gene encoding glycine decarboxylase) with so-called augmentation of the antipsychotic clozapine by the NMDA receptor co-agonists glycine and D-serine and thus explicitly links an individual mutation to the pathophysiology of psychosis and treatment response. In other words, this CNV is one of the very rare examples identified in humans where a (genomic) mutation affects a core pathway of the pathophysiology of schizophrenia.
Strain Development
The donor constructed mice with a 0.9-Mb deletion on mouse chromosome 19 syntenic with the human 9p24.1 region by trans-allelic recombination in vivo. The deletion includes the genes Rln1, Plgrkt, Cd274, Pdcd1lg2, Ric1, Ermp1, Mlana, 9930021J03Rik, Ranbp6, Il33, Trpd52l3, Uhrf2, and Gldc. Briefly, the donor inserted loxP sites into the mouse genome by targeting sites to flank the region to duplicate or delete. Mice were bred that carry the two loxP sites in trans and an Hprt-Cre transgene (RRID:IMSR_JAX:004302). When breeding these mice to wild-type mice, the donor obtained offspring that carried either the duplication or the deletion, demonstrating trans-allelic recombination in the germline. Both deletion and duplication alleles were confirmed by PCR and by comparative genomic hybridization. The selectable neo marker was deleted by Flp/FRT-mediated recombination in the germline (RRID:IMSR_JAX:003800). Gene targeting was performed in V6.5 ES cells (C57BL/6J x 129S4/SvJae), and mice were backcrossed to the C57BL/6J background for at least 10 generations.
Suggested Control Mice
Wild-type littermates from breeding hemizygous mice with C57BL/6J wild-type mice.
MMRRC Genetic QC Summary
The MMRRC Centers have developed a genetic QC pipeline using MiniMUGA array genotyping to provide additional information on strain backgrounds for MMRRC congenic and inbred strains. For more information on when data may be available, or to request genotyping for a strain of interest, please contact mmrrc@missouri.edu. Older strains may not have this information.
  • Models for Human Disease
  • Neurobiology
Donor
Uwe Rudolph, M.D., University of Illinois at Urbana-Champaign.
Primary Reference
Not ready to publish
Additional References

Tcw J, Carvalho CMB, Yuan B, Gu S, Altheimer AN, McCarthy S, Malhotra D, Sebat J, Siegel AJ, Rudolph U, Lupski JR, Levy DL, Brennand KJ. Divergent Levels of Marker Chromosomes in an hiPSC-Based Model of Psychosis. Stem Cell Reports. 2017 Mar 14;8(3):519-528. doi: 10.1016/j.stemcr.2017.01.010. Epub 2017 Feb 16. (Medline PMID: 28216146)

Bodkin JA, Coleman MJ, Godfrey LJ, Carvalho CMB, Morgan CJ, Suckow RF, Anderson T, Öngür D, Kaufman MJ, Lewandowski KE, Siegel AJ, Waldstreicher E, Grochowski CM, Javitt DC, Rujescu D, Hebbring S, Weinshilboum R, Rodriguez SB, Kirchhoff C, Visscher T, Vuckovic A, Fialkowski A, McCarthy S, Malhotra D, Sebat J, Goff DC, Hudson JI, Lupski JR, Coyle JT, Rudolph U, Levy DL. Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene. Biol Psychiatry. 2019 Oct 1;86(7):523-535. doi: 10.1016/j.biopsych.2019.04.031. Epub 2019 May 9. (Medline PMID: 31279534)

Grochowski CM, Gu S, Yuan B, Tcw J, Brennand KJ, Sebat J, Malhotra D, McCarthy S, Rudolph U, Lindstrand A, Chong Z, Levy DL, Lupski JR, Carvalho CMB. Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes. Hum Mutat. 2018 Jul;39(7):939-946. doi: 10.1002/humu.23537. Epub 2018 May 11. (Medline PMID: 29696747)

Colony and Husbandry Information

Colony Surveillance Program and Current Health Reports

Mice recovered from a cryo-archive will have health surveillance performed on recipient females. Health reports will be provided prior to shipment. If you require additional health status information, please email mmrrc@missouri.edu.
Coat Color
Black
Eye
Black
MMRRC Breeding System
Backcross
Generation
N10+ (C57BL/6J)
Overall Breeding Performance
Excellent
Viability and Fertility: Female Male Comments
Homozygotes are viable: Yes Yes
Homozygotes are fertile: Yes Yes
Heterozygotes are fertile: Yes Yes
Age Reproductive Decline: 10 to 12 months 10 to 12 months
Bred to Homozygosity
Yes
Average litter size
4 to 6
Recommended wean age
3 Weeks
Average Pups Weaned
4 to 6

Order Request Information

Limited quantities of breeder mice (recovered litter) are available from a cryoarchive; recovered litter usually available to ship in 3 to 4 months.

Cryopreserved material may be available upon request, please inquire to mmrrc@missouri.edu for more information.

A Commercial License Agreement from the Donor is required for for-profit entities to use this strain. For more information, please contact Sherene Shenouda.

Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.

A Commercial License Agreement from the Donor is required for for-profit entities to use this strain. For more information, please contact Sherene Shenouda

Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.

Click button to Request this one strain. (Use the MMRRC Catalog Search to request more than one strain.)
MMRRC Item # Description Distribution Fee / Unit (US $)
*Shipping & Handling not included*
Units Notes
068238-MU-SPERM Cryo-preserved spermatozoa $437.00 / $817.00
Non-Profit / For-Profit
Aliquot Approximate quantity3
068238-MU-RESUS Litter recovered from cryo-archive $2,624.00 / $5,340.00
Non-Profit / For-Profit
Litter Recovered litter4; additional fees for any special requests.
Cryopreserved material may be available upon request, please inquire to mmrrc@missouri.edu for more information.

Some MMRRC strains were submitted by the donor as cryopreserved germplasm, and because these strains were not cryopreserved by the MMRRC, we have not assessed the quality, nor genotype, of this material. Our expertise in reviving mice from various qualities of frozen sperm and embryos, using methods like IVF and ICSI, gives us confidence in successful recoveries in most cases. However, due to the uncertain quality of these samples, we'll limit revival attempts to two per order. Additional attempts are available for a fee, on top of standard charges, if requested. It's important to note that some strains may lack the expected mutation, so we can't assure successful order fulfillment until we attempt to revive the strain.

1 The distribution fee covers the expense of rederiving mice from a live mouse; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

2 An aliquot contains a sufficient number of embryos (in one or more vials or straws and based on the transfer success rate of the MMRRC facility) to transfer into one to three recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.

3 An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.

4 The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.